Indazole derivatives having monocyclic amine

ABSTRACT

An indazole compound having the formula (I): wherein: 
     R 1  is hydrogen, C 1  -C 6  alkyl, C 3  -C 6  alkenyl or C 3  -C 6  cycloalkyl; 
     Q is carbonyl, thiocarbonyl or methylene; and 
     R 2  is a group of the formula (II) or (IV); ##STR1##  wherein R 1  is C 1  -C 6  alkyl, C 3  -C 6  alkenyl or benzyl, of which a phenyl group thereof is optionally mono- or di-substituted by the same or different halogen or methoxy; m is 0 to 2; n and o is 1 or 2. The compound exhibits 5-HT 4  receptor agonist activity.

TECHNICAL FIELD

This invention relates to a new indazole derivative having a monocyclicamine, a pharmaceutically acceptable salt thereof and a process for thepreparation thereof.

The invention further relates to a 5-HT₄ receptor agonist, inparticular, an agent for the treatment of digestive tract diseases whichcomprise as an active ingredient the indazole derivative or the saltthereof.

The invention furthermore relates to a method for the treatment ofgastrointestinal disorders which comprises administering the indazolederivative or the salt thereof to the patients suffering fromgastrointestinal disorders.

BACKGROUND ART

The abnormality in a gastrointestinal motor function by various causessuch as chronic gastritis, gastrectomy, peptic ulcer, diabetes mellitusor scleroderma results in the reflux of gastric contents into theesophagus, delayed emptying of the contents and the depression of smalland large intestinal functions.

This can lead to several gastrointestinal disorders including nausea,vomiting, heartburn, anorexia, abdominal distension, epigastricdysphoria, abdominaglia, constipation and further reflux esophagitis.One cause of the diseases such as irritable bowel syndrome and spuriousileus is considered to be the depression in gastrointestinal motility.

The agents for the treatment of these conditions and diseases includedirect cholinergic agent (e.g. Aclatonium Napadisilate) or Dopamineantagonist (e.g. Domperidone).

However, it is known that these known agents have the problems ofinsufficent therapeutic effects and side effects including diarrhea andextrapyramidal syndrome.

The gastrointestinal motility is controlled by both sympathetic andparasympathetic nervous systems. In the parasympathetic nervous system,acetylcholine is one of the most important neurotransmittersparticipating in the control of gastrointestinal motility. The releaseof acetylcholine from the nerves in the nerve plexus of gastrointestinaltract may induce the contraction of gastrointestinal tract. Accordingly,the accelerated release of acetylcholine from the nerve plexus ofgastrointestinal tract results in sthenia of gastrointestinal motility.

Recently, a 5-HT₄ receptor was found in gastrointestinal tract. The5-HT₄ receptor was reported to control the release of acetylcholine inthe gastrointestinal nerve Trends in Pharmacological Science, Vol. 13,141-145, (1992)!. Thus, compounds acting on the 5-HT₄ receptor in thegastrointestinal tract and promoting the release of acetylcholine may bea more effective gastrokinetic agent with less side effects.

On the other hand, WO 9303725 discloses that(1-butyl-4-piperidyl)methyl-1-methylindazole-3-carboxylate (Example 10)has a 5-HT₄ receptor antagonist activity, and is of potential use in thetreatment of diseases derived from 5-HT, diarrhea of irritable bowelsyndrome due to the 5-HT activated intestinal nerve, cardiovasculardisorders and CNS disorders. U.S. Pat. No. 3,145,215 discloses that N-2-(4-methyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide hashypotensive activity. However, it is not reported that those compoundshave 5-HT₄ receptor agonist activities and gastrointestinal prokineticactions.

Aliment. Pharmacol. Ther., Vol. 6, 273-289, 1992 suggests that irritablebowel syndrome exists as two types, constipation-type and diarrhea-typeirritable bowel syndromes and 5-HT₄ receptor agonists are useful in thetreatment of constipation-type irritable bowel syndrome, while MedicinalResearch Reviews, Vol. 13, 633-662, 1993 suggests that 5-HT₄ receptorantagonists are useful in the treatment of diarrhea-type irritable bowelsyndrome.

WO 9312785 discloses that 5-HT₄ receptor antagonists and agonists are ofpotential use in the treatment of conditions associated with bladderhypersensitivity and a poorly functioning bladder.

By elucidation of new compounds having a 5-HT₄ receptor agonistactivity, it has been demanded to develop a medicine based on such amechanism of action that acts on the 5-HT₄ receptor controlling therelease of acetylcholine in the gastrointestinal nerve to promote therelease of acetylcholine from the nerves in the nerve plexus ofgastrointestinal tract, resulting in sthenia of a gastrointestinalmotion, i.e., a 5-HT₄ receptor agonist.

DISCLOSURE OF INVENTION

As a result of our zealous search to solve such problems, we have foundthat the monocyclic amines, i.e., 4-piperidyl derivatives,2-(4-piperidyl)ethyl derivatives, 2-(1-piperazinyl)ethyl derivatives,2-(4-piperidylidene)-ethyl derivatives and 5-octahydroazocinylderivatives have a prominent 5-HT₄ receptor agonist activity, andexhibit a gastrointestinal prokinetic action, which are effective forthe treatment of the abnormality in function of a gastrointestinalmotility by various causes such as chronic gastritis, gastrectomy,peptic ulcer, diabetes mellitus, scleroderma, and digestive tractdiseases such as reflux esophagitis, irritable bowel syndrome withconstipation as a chief complaint and spurious ileus.

The present invention provides an indazole derivative having amonocyclic amine, represented by formula ##STR2## wherein R₁ is ahydrogen atom, a C₁ -C₆ alkyl group, a C₃ -C₅ alkenyl group or a C₃ -C₆cycloalkyl group,

Q is a carbonyl group, a thiocarbonyl group or a methylene group,

R₂ represents a group of formula (II), (III), (IV) or (V) ##STR3##wherein R₃ is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzylgroup, of which a phenyl ring may be substituted by the same ordifferent halogen atom or methoxy group, m is 0-2, n is 2 or 3, o is 1or 2, p is 2-4, and a pharmaceutically acceptable salt thereof.

In formula (I) for the indazole derivative having a monocyclic amine ofthe present invention, examples of the C₁ -C₆ alkyl group represented byR₁ include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, (S)-sec-butyl, (R)- sec-butyl, tert-butyl, pentyl, isopentyl,2-pentyl, 3-pentyl, neo-pentyl, tert-pentyl, hexyl and the like.Examples of the C₃ -C₆ alkenyl group include allyl, 2-butenyl,3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 3-methyl-2-butenyland the like. Examples of the C₃ -C₆ cycloalkyl group includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examplesof the C₁ -C₆ alkyl group represented by R₃ include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, tert-pentyl, hexyl and thelike. Examples of the C₃ -C₆ alkenyl group include allyl, 2-butenyl,3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 3-methyl-2-butenyland the like. Examples of the benzyl group and mono- or di-substitutedbenzyl group include benzyl, o-fluorobenzyl, m-fluorobenzyl,p-fluorobenzyl, 2,3-difluorobenzyl, 2,4-difluorobenzyl,2,5-difluorobenzyl, 2,6-difluorobenzyl, 3,4-difluorobenzyl,3,5-difluorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl,2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl,2,6-dichlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl,o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, 2,3-dibromobenzyl,2,4-dibromobenzyl, 2,5-dibromobenzyl, 2,6-dibromobenzyl,3,4-dibromobenzyl, 3,5-dibromobenzyl, o-iodobenzyl, m-iodobenzyl,p-iodobenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl,2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl,2,6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl and thelike.

The compounds of formula (I) according to the present invention can beprepared by various processes which will be explained below.

The compounds of formula (I^(I)) ##STR4## wherein R₁ ' is a C₁ -C₆ alkylgroup or a C₃ -C₆ alkenyl group,

Q¹ is a carbonyl group,

R₂ represents a group having each of formulae (II)-(V) ##STR5## whereinR₃ is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzyl group, ofwhich a phenyl ring may be mono- or di-substituted by the same ordifferent halogen atom or methoxy group, m is 0-2, n is 2 or 3, o is 1or 2 and p is 2-4, can be prepared by reacting an indazole-3-carboxylicacid derivative of formula (VI) ##STR6## wherein R₁ ' is a C₁ -C₆ alkylgroup or a C₃ -C₆ alkenyl group and X is OH, with an amine derivativehaving each of formulae (VII)-(X) ##STR7## wherein R₃, m, n, o and phave the meanings as defined above, in the presence of a condensingagent such as carbodiimide derivatives or dialkylphosphorocyanidatederivatives.

Alternatively, the compounds of formula (I^(I)) can be prepared byreacting an indazole-3-carboxylic acid derivative of formula (VI)##STR8## wherein R₁ ' is a C₁ -C₆ alkyl group or a C₃ -C₆ alkenyl groupand X is a halogen atom or R₄ COO wherein R₄ is an alkyl group such asmethyl or a haloalkyl group such as trifluoromethyl, or its reactivederivative with an amine derivative having each of formulae (VII)-(X)##STR9## wherein R₃, m, n, o and p have the meanings as defined above,in the presence of a base.

The compounds of formula (I^(II)) ##STR10## wherein Q_(I) is a carbonylgroup,

R₂ represents a group having each of formulae (II)-(V) ##STR11## whereinR₃, m, n, o and p have the meanings as defined above can be prepared byreacting an indazole-3-carboxylic acid of formula (VI^(I)) ##STR12## orits dimer, i.e., a diindazolo 2,3-a! 2', 3'-d!pyrazine-7,14-dione offormula (XI) ##STR13## with an amine derivative having each of formulae(VII)-(X) ##STR14## wherein R₃, m, n, o and p have the meanings asdefined above.

The compounds of formula (I^(I)) ##STR15## wherein R₁ ' is a C₁ -C₆alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₆ cycloalkyl group, Q^(I)is a carbonyl group, and R₂ has the meaning as defined above, can beprepared by reacting the compounds of formula (I^(II)) as obtained abovewith an alkylhalide or alkenylhalide of formula (XII)

    R.sub.1 'Y                                                 (XII)

wherein R₁ ' is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₅cycloalkyl group and Y is a halogen atom in the presence of a base, orby reacting the compound of formula (I^(II)) with an alkylalcohol, analkenylalcohol or a cycloalkylalcohol of formula (XII)

    R.sup.1 'Y                                                 (XII)

wherein R₁ is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₆cycloalkyl group and Y is OH, and a di(C₁ -C₆)alkylazodicarboxylate inthe presence of a tri-substituted phosphine.

The compounds of formula (I^(III)) ##STR16## wherein R₁ is a hydrogenatom, a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₆cycloalkyl group, Q^(I) is a carbonyl group and R₂ ' represents a grouphaving each of the following formulae (II^(I))-(V^(I)) ##STR17## whereinm, n, o and p have the meanings as defined above and R₃ ' is a methylgroup or a benzyl group, of which a phenyl ring may be substituted, aresubjected to demetylation or debenzylation to give the compounds offormula (I^(II)) wherein R₃ ' is a hydrogen atom, which are then reactedwith a compound of formula (XIII)

    R.sub.3 Z                                                  (XIII)

wherein R₃ is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzylgroup, of which a phenyl ring may be mono- or di-substituted by the sameor different halogen atom or methoxy group and Z is a halogen atom, thuspreparing the compounds of formula (I^(I)) wherein R₃ has the meaning asdefined above.

The compounds of formula (I^(IV)) ##STR18## wherein R₁ ' is a C₁ -C₆alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₆ cycloalkyl, Q^(II) is athiocarbonyl group and R₂ represents a group of formula (III) ##STR19##wherein R₃ is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzylgroup, of which a phenyl ring may be substituted by the same ordifferent halogen atom or methoxy group and n is 2 or 3 can be preparedby reacting the compounds of formula (I^(I)) wherein Q^(I) is a carbonylgroup and R₁ ' and R₂ have the meanings as defined above, with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(called hereafter "Lawesson reagent") of formula (XIV) ##STR20##

The compounds of formula (I^(V)) ##STR21## wherein R₁ ' is a C₁ -C₆alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₆ cycloalkyl group,Q^(III) is a methylene group and R₂ represents the following formula(III) ##STR22## wherein R₃ is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenylgroup or a benzyl group, of which a phenyl ring may be mono- ordi-substituted by the same or different halogen atom or methoxy groupand n is 2 or 3 can be prepared by reacting the compounds of formula(I^(I)) wherein Q^(I) is a carbonyl group and R₁ ' and R₂ have themeanings as defined above, with a reducing agent such as lithiumaluminum hydride.

The above reactions are shown in Scheme 1. ##STR23## --R₂ '--R₃ standsfor a group represented by formulae (II)-(V).

Further, the processes for preparing the compounds of the invention willbe illustrated in detail.

In the condensation of the indazole-3-carboxylic acids of formula (VI)##STR24## wherein R₁ ' is a C₁ -C₆ alkyl group or a C₃ -C₆ alkenyl groupand X is OH, or their derivatives with the amine derivatives having eachof formulae (VII)-(X) ##STR25## wherein R₃, m, n, o and p have themeanings as defined above, the reaction is carried out using 0.1-10moles, preferably 0.5-2 moles of the indazole-3-carboxylic acids ortheir derivatives per mole of the amine derivatives, in the presence of0.1-10 moles, preferably 0.5-2 moles of a condensing agent such asdialkyl phosphorocyanidate or carbodiimide derivative. In this reaction,0.5-2 moles of 1-hydroxybenzotriazole (monohydrate) orN-hydroxysuccinimide may be used, if necessary. The reaction may becarried out at a temperature between the freezing point and the boilingpoint of the solvent, preferably at 0-40° C. Any solvent which isinactive in the reaction can be used, which can include hydrocarbonssuch as pentane, hexane, heptane, cyclohexane, petroleum ether, benzeneand the like; halogenated hydrocarbons such as carbon tetrachloride,chloroform, methylene chloride and the like; ethers such as ethyl ether,THF, dioxane and the like; esters such as ethyl acetate and the like;acetone; DMF; DMSO; and nitromethane, but methylene chloride and DMF arepreferred.

Examples of the indazole-3-carboxylic acids or their derivatives includethe following:

indazole-3-carboxylic acid,

1-methylindazole-3-carboxylic acid,

1-ethylindazole-3-carboxylic acid,

1-propylindazole-3-carboxylic acid,

1-isopropylindazole-3-carboxylic acid,

1-butylindazole-3-carboxylic acid,

1-isobutylindazole-3-carboxylic acid,

1-(sec-butyl)indazole-3-carboxylic acid,

(S)-1-(sec-butyl)indazole-3-carboxylic acid,

(R)-1-(sec-butyl)indazole-3-carboxylic acid,

1-pentylindazole-3-carboxylic acid,

1-isopentylindazole-3-carboxylic acid,

1-(2-pentyl)indazole-3-carboxylic acid,

1-(3-pentyl)indazole-3-carboxylic acid,

1-(neo-pentyl)indazole-3-carboxylic acid,

1-allylindazole-3-carboxylic acid,

1-(2-butenyl)indazole-3-carboxylic acid,

1-(3-butenyl)indazole-3-carboxylic acid,

1-(2-methyl-2-propenyl)indazole-3-carboxylic acid,

1-(1-methyl-2-propenyl)indazole-3-carboxylic acid,

1-(3-methyl-2-butenyl)indazole-3-carboxylic acid,

1H-indazole-3-carboxylic acid and the like.

Examples of the amine derivatives include the following:

4-piperidylamine,

1-methyl-4-piperidylamine,

1-butyl-4-piperidylamine,

1-benzyl-4-piperidylamine,

(4-piperidyl)methylamine,

(1-methyl-4-piperidyl)methylamine,

(1-butyl-4-piperidyl)methylamine,

2-(1-methyl-4-piperidyl)ethylamine,

2-(1-butyl-4-piperidyl)ethylamine,

2-(4-methyl-1-piperazinyl)ethylamine,

2-(4-butyl-1-piperazinyl)ethylamine,

2-(4-p-fluorobenzyl-1-piperazinyl)ethylamine,

3-(4-butyl-1-piperazinyl)propylamine,

2-(1-methyl-4-piperidylidene)ethylamine,

2-(1-butyl-4-piperidylidene)ethylamine,

2-(1-p-fluorobenzyl-4-piperidylidene)ethylamine,

1-butyl-4-hexahydroazepinylamine,

1-butyl-5-octahydroazocinylamine,

1-butyl-5-octahydroazoninylamine and the like.

Examples of the dialkyl phosphorocyanidate derivatives include diethylphosphorocyanidate and the like.

Examples of the carbodiimide derivatives can includedicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride and the like.

In the reaction of the reactive derivatives of the indazole-3-carboxylicacids of formula (VI) ##STR26## wherein R₁ ' is a C₁ -C₆ alkyl group ora C₃ -C₆ alkenyl group and X is a halogen atom or R₄ COO wherein R₄ isan alkyl group such as methyl or a haloalkyl group such astrifluoromethyl, or the dimer of indazole-3-carboxylic acid representedby formula (XI) ##STR27## with the amine derivatives having each offormulae (VII)-(X) ##STR28## wherein R₃, m, n, o and p have the meaningsas defined above, the reaction is carried out by using 0.1-10 moles,preferably 0.25-2 moles of the reactive derivatives of theindazole-3-carboxylic acids or the dimer of indazole-3-carboxylic acidper mole of the amine derivatives. The reaction may be carried out at atemperature between the freezing point and the boiling point of thesolvent, preferably at 0-40° C. Any solvent which is inactive in thereaction can be used, which can include hydrocarbons such as pentane,hexane, heptane, cyclohexane, petroleum ether, benzene and the like;halogenated hydrocarbons such as carbon tetrachloride, chloroform,methlene chloride and the like; ethers such as diethyl ether, THF,dioxane and the like; esters such as ethyl acetate and the like;acetone; DMF, nitromethane; DMSO; HMPA; pyridine and the like, but DMFand DMSO are preferred. In this reaction, bases such asdimethylaminopyridine, triethylamine, pyridine, potassium carbonate,sodium carbonate and the like may be used, if necessary.

Examples of the reactive derivatives of indazole-3-carboxylic acidsinclude the following:

1-methylindazole-3-carbonyl chloride,

1-ethylindazole-3-carbonyl chloride,

1-propylindazole-3-carbonyl chloride,

1-isopropylindazole-3-carbonyl chloride

1-butylindazole-3-carbonyl chloride,

1-isobutylindazole-3-carbonyl chloride,

1-(sec-butyl)indazole-3-carbonyl chloride,

(S)-1-(sec-butyl)indazole-3-carbonyl chloride,

(R)-1-(sec-butyl)indazole-3-carbonyl chloride,

1-(n-pentyl)indazole-3-carbonyl chloride,

1-isopentylindazole-3-carbonyl chloride,

1-(2-pentyl)indazole-3-carbonyl chloride,

1-(3-pentyl)indazole-3-carbonyl chloride,

1-(neo-pentyl)indazole-3-carbonyl chloride,

1-allylindazole-3-carbonyl chloride,

1-(2-butenyl)indazole-3-carbonyl chloride,

1-(3-butenyl)indazole-3-carbonyl chloride,

1-(2-methyl-2-propenyl)indazole-3-carbonyl chloride,

1-(1-methyl-2-propenyl)indazole-3-carbonyl chloride,

1-(3-methyl-2-butenyl)indazole-3-carbonyl chloride,

diindazolo 2,3-a! 2',3'-d!pyrazine-7,14-dione and the like.

In the reaction of the 1H-indazole-3-carboxamide derivatives of formula(I^(II)) ##STR29## wherein Q^(I) is a carbonyl group, R₂ has the meaningas defined above, with the halides of formula (XII)

    R.sub.1 'Y                                                 (XII)

wherein R₁ ' is a C₁ -C₆ alkyl group or a C₃ -C₆ alkenyl group and Y isa halogen atom, the reaction is carried out by using 0.1-10 moles,preferably 0.5-3 moles of the halides per mole of the1H-indazole-3-carboxamide derivatives in the presence of 0.1-10 moles,preferably 0.8-1.2 moles of a base. The reaction may be carried out at atemperature between the freezing point and the boiling point of thesolvent, preferably at 0-40° C. Any solvent which is inactive in thereaction can be used, which can include hydrocarbons such as pentane,hexane, heptane, cyclohexane, petroleum ether, benzene and the like;ethers such as diethyl ether, THF, dioxane and the like; esters such asethyl acetate and the like; DMF; DMSO and the like, but DMF ispreferred.

Examples of the 1H-indazole-3-carboxamide derivatives include thefollowing:

N-(4-piperidyl)-1H-indazole-3-carboxamide,

N-(1-methyl-4-piperidyl)-1H-indazole-3-carboxamide,

N-(1-butyl-4-piperidyl)-1H-indazole-3-carboxamide,

N-(1-benzyl-4-piperidyl)-1H-indazole-3-carboxamide,

N-(4-piperidyl)methyl-1H-indazole-3-carboxamide,

N-(1-methyl-4-piperidyl)methyl-1H-indazole-3-carboxamide,

N-(1-butyl-4-piperidyl)methyl-1H-indazole-3-carboxamide,

N- 2-(1-methyl-4-piperidyl)ethyl!-1H-indazole-3-carboxamide,

N- 2-(1-butyl-4-piperidyl)ethyl!-1H-indazole-3-carboxamide,

N- 2-(4-methyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide,

N- 2-(4-butyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide,

N- 2-(4-p-fluorobenzyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide,

N- 3-(4-butyl-1-piperazinyl)propyl!-1H-indazole-3-carboxamide,

N- 2-(1-methyl-4-piperidylidene)ethyl!-1H-indazole-3-carboxamide,

N- 2-(1-butyl-4-piperidylidene)ethyl!-1H-indazole-3-carboxamide,

N-2-(1-p-fluorobenzyl-4-piperidylidene)ethyl!-1H-indazole-3-carboxamide,

N-(1-butyl-4-hexahydroazepinyl)-1H-indazole-3-carboxamide,

N-(1-butyl-5-octahydroazocinyl)-1H-indazole-3-carboxamide and the like.

Examples of the halides include methyl iodide, ethyl bromide, ethyliodide, propyl bromide, isopropyl chloride, isopropyl bromide, isopropyliodide, butyl bromide, isobutyl chloride, isobutyl bromide, isobutyliodide, sec-butyl chloride, sec-butyl bromide, sec-butyl iodide,(S)-sec-butyl chloride, (S)-sec-butyl bromide, (S)-sec-butyl iodide,(R)-sec-butyl chloride, (R)-sec-butyl bromide, (R)-sec-butyl iodide,pentyl bromide, isopentyl bromide, 2-pentyl bromide, 3-pentyl bromide,neo-pentyl bromide, allyl bromide, 2-butenyl bromide, 3-butenyl bromide,2-methyl-2-propenyl bromide, 1-methyl-2-propenyl bromide,3-methyl-2-butenyl bromide and the like.

Examples of the bases include sodium hydride, butyl lithium and thelike.

In the reaction of the 1H-indazole-3-carboxamide derivatives of formula(I^(II)) ##STR30## wherein Q^(I) is a carbonyl group, R₂ has the meaningas defined above with the alcohols of formula (XII)

    R.sub.1 'Y                                                 (XII)

wherein R₁ ' is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₆cycloalkyl group and Y is OH, the reaction is carried out by using 0.5-2moles, preferably 0.8-1.2 moles of the dialkylazodicarboxylate, 0.5-2moles, preferably 0.8-1.2 moles of the tri-substituted phosphine and0.5-2 moles, preferably 0.8-1.2 moles of the RX' per mole of the1H-indazole-3-carboxamide derivatives. The reaction may be carried outat a temperature between the freezing point and the boiling point of thesolvent, preferably at 0-100° C. Any solvents which is inactive in thereaction can be used and ethers such as diethyl ether, THF, dioxane andthe like, and DMF are preferably used.

Examples of the alcohols include methanol, ethanol, propanol, isopropylalcohol, butanol, isobutyl alcohol, sec-butyl alcohol, (S)-sec-butylalcohol, (R)-sec-butyl alcohol, pentyl alcohol, isopentyl alcohol,2-pentyl alcohol, 3-pentyl alcohol, neo-pentyl alcohol, allyl alcohol,cyclobutanol, cyclopentanol, cyclohexanol and the like.

Examples of the dialkylazodicarboxylates includediethylazodicarboxylate, diisopropylazodicarboxylate and the like.

Examples of the tri-substituted phosphines include triphenylphosphine,tributylphosphine and the like.

Debenzylation of the benzyl derivatives represented by formula (I^(III))##STR31## wherein R₁ is a hydrogen atom, a C₁ -C₆ alkyl group, a C₃ -C₆alkenyl group or a C₃ -C₆ cycloalkyl group, Q^(I) is a carbonyl groupand R₂ ' represents a group having each of formulae (II^(I))-(V^(I))##STR32## wherein R₃ ' is a benzyl group, m, n, o and p have themeanings as defined above, is carried out in the presence of a catalystin a hydrogen atmosphere. The reaction is carried out at a pressurebetween ordinary pressure and 200 kg/cm², preferably between ordinarypressure and 100 kg/cm², at a temperature between the freezing point andthe boiling point of the solvent, preferably at 0-100° C. The solventswhich are preferably employed include alcohols such as methanol,ethanol, propanol, isopropyl alcohol and the like; water; and DMF.

Examples of the benzyl derivatives include the following:

N-(1-benzyl-4-piperidyl)-1-propylindazole-3-carboxamide,

N-(1-benzyl-4-piperidyl)methyl-1-propylindazole-3-carboxamide,

N- 2-(1-benzyl-4-piperidyl)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(4-benzyl-1-piperazinyl)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(4-benzyl-1-piperazinyl)ethyl!-1-sec-butylindazole-3-carboxamide,

N- 2-(4-benzyl-1-piperazinyl)ethyl!-1-(3-pentyl)indazole-3-carboxamide,

N- 2-(4-benzyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide,

N- 2-(4-benzyl-1-piperazinyl)ethyl!-1-allylindazole-3-carboxamide,

N- 2-(1-benzyl-4-piperidylidene)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(1-benzyl-4-piperidylidene)ethyl!-1H-indazole-3-carboxamide,

N-(1-benzyl-4-hexahydroazepinyl)-1-propylindazole-3-carboxamide,

N-(1-benzyl-5-octahydroazocinyl)-1-propylindazole-3-carboxamide,

N-(1-benzyl-5-octahydroazoninyl)-1-propylindazole-3-carboxamide and thelike.

Examples of the catalysts include palladium-carbon, palladium hydroxide,Raney nickel and platinum (IV) oxide and the like.

Demethylation of the methyl derivatives represented by formula (I^(III))##STR33## wherein R₁ is a hydrogen atom, a C₁ -C₆ alkyl group, a C₃ -C₆alkenyl group or a C₃ -C₆ cycloalkyl, Q_(I) is a carbonyl group and R₂ 'represents a group having each of formulae (II^(I))-(V^(I)) ##STR34##wherein R₃ ' is a methyl group, m, n, o and p have the meanings asdefined above, is carried out at a temperature of 0° to 200° C.,preferably between room temperature and 120° C. in α-chloroethylchloroformate.

Examples of the methyl derivatives include the following;

N-(1-methyl-4-piperidyl)-1-propylindazole-3-carboxamide,

N-(1-methyl-4-piperidyl)methyl-1-propylindazole-3-carboxamide,

N- 2-(1-methyl-4-piperidyl)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(4-methyl-1-piperazinyl)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(4-methyl-1-piperazinyl)ethyl!-1-sec-butylindazole-3-carboxamide,

N- 2-(4-methyl-1-piperazinyl)ethyl!-1-(3-pentyl)indazole-3-carboxamide,

N- 2-(4-methyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide,

N- 2-(4-methyl-1-piperazinyl)ethyl!-1-allylindazole-3-carboxamide,

N- 2-(1-methyl-4-piperidylidene)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(1-methyl-4-piperidylidene)ethyl!-1H-indazole-3-carboxamide,

N-(1-methyl-4-hexahydroazepinyl)-1-propylindazole-3-carboxamide,

N-(1-methyl-5-octahydroazocinyl)-1-propylindazole-3-carboxamide,

N-(1-methyl-5-octahydroazoninyl)-1-propylindazole-3-carboxamide and thelike.

The reaction of the compounds of formula (I^(IV)) with the halides offormula (XIII)

    R.sub.3 Z                                                  (XIII)

wherein R₃ is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzylgroup, of which a phenyl ring may be mono- or di-substituted by the sameor different halogen atom or methoxy group, Z is a halogen atom canintroduce the R₃ group as defined above into the demethylated ordebenzylated derivatives of formula (I^(VI)) ##STR35## wherein R₁ is ahydrogen atom, a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₆cycloalkyl, Q^(I) is a carbonyl group and R₂ represents a group havingeach of formulae (II^(II))-(V^(II)) ##STR36## wherein R³ ' is a hydrogenatom, m, n, o and p have the meanings as defined above. The reaction iscarried out at a temperature of 0-200° C., preferably between roomtemperature and 130° C. Any solvent which is inactive in the reactioncan be used, which include alcohols such as methanol, ethanol, propanol,isopropyl alcohol, ethylene glycol and the like; chloroform, methylenechloride, DMF, acetonitrile, acetone, DMSO, HMPA and DMI. The reactionis also carried out, if necessary, in the presence of bases such asdimetylaminopyridine, triethylamine, pyridine, potassium carbonate,sodium carbonate and the like or fluorine-compounds such as potassiumfluoride-cellite, lithium fluoride, sodium fluoride, cesium fluoride,rubidium fluoride and the like. Further, in case of usingfluorine-compounds, crown ethers such as 18-crown-6, 15-crown-5 and thelike may be used.

Alternatively, the introduction of the methyl group into theabove-mentioned debenzylated derivatives may be achieved by performingthe reaction under the condition from room temperature to reflux-heatingin formic acid-formaldehyde.

Examples of the demethylated or debenzylated derivatives include thefollowing:

N-(4-piperidyl)-1-propylindazole-3-carboxamide,

N-(4-piperidyl)methyl-1-propylindazole-3-carboxamide,

N- 2-(4-piperidyl)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(1-piperazinyl)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(1-piperazinyl)ethyl!-1-sec-butylindazole-3-carboxamide,

N- 2-(1-piperazinyl)ethyl!-1-(3-pentyl)indazole-3-carboxamide,

N- 2-(1-piperazinyl)ethyl!-1H-indazole-3-carboxamide,

N- 2-(1-piperazinyl)ethyl!-1-allylindazole-3-carboxamide,

N- 2-(-4-piperidylidene)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(4-piperidylidene)ethyl!-1H-indazole-3-carboxamide,

N-(4-hexahydroazepinyl)-1-propylindazole-3-carboxamide,

N-(5-octahydroazocinyl)-1-propylindazole-3-carboxamide,

N-(5-octahydroazoninyl)-1-propylindazole-3-carboxamide and the like.

Examples of the halides include methyl iodide, ethyl bromide, ethyliodide, propyl bromide, isopropyl chloride, isopropyl bromide, isopropyliodide, butyl bromide, isobutyl chloride, isobutyl bromide, isobutyliodide, sec-butyl chloride, sec-butyl bromide, sec-butyl iodide,(S)-sec-butyl chloride, (S)-sec-butyl bromide, (S)-sec-butyl iodide,(R)-sec-butyl chloride, (R)-sec-butyl bromide, (R)-sec-butyl iodide,pentyl bromide, isopentyl bromide, 2-pentyl bromide, 3-pentyl bromide,neo-pentyl bromide, allyl bromide, 2-butenyl bromide, 3-butenyl bromide,2-methyl-2-propenyl bromide, 1-methyl-2-propenyl bromide,3-methyl-2-butenyl bromide, p-fluorobenzyl chloride, p-chlorobenzylchloride, p-bromobenzyl bromide, o-iodobenzyl chloride, p-methoxybenzylchloride and the like.

The indazole-3-carboxamide derivatives represented by formula (I^(I))##STR37## wherein R₁ ' is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl groupor a C₃ -C₆ cycloalkyl group, Q^(I) is a carbonyl group, R₂ represents agroup having each of formulae (II)-(V) ##STR38## wherein R₃ is a C₁ -C₆alkyl group, a C₃ -C₆ alkenyl group or a benzyl group, of which a phenylring may be mono- or di-substituted by the same or different halogenatom or methoxy group, m, n, o and p have the meanings as defined abovecan be converted into the thioamide derivatives with 1-10 moles,preferably 1-2 moles of Lawesson's reagent represented by formula (XIV)##STR39## per mole of the indazole-3-carboxamide derivatives. Thereaction may be carried out at a temperature between the freezing pointand the boiling point of the solvent, preferably between roomtemperature and the boiling point of the solvent. Any solvent which isinactive in the reaction can be used, which include chloroform,methylene chloride, benzene, toluene, acetonitrile and the like.

The carbonyl group of the indazole-3-carboxamide derivatives representedby formula ##STR40## wherein R₁ ' is a C₁ -C₆ alkyl group, a C₃ -C₆alkenyl group or a C₃ -C₆ cycloalkyl group, Q_(I) is a carbonyl group,R₂ represents a group having each of formulae (II)-(V) ##STR41## whereinR₃ is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzyl group, ofwhich a phenyl ring may be mono- or di-substituted by the same ordifferent halogen atom or methoxy group, m, n, o and p have the meaningsas defined above, can be converted into the methylene group with 1-10moles, preferably 1-3 moles of a reducing agent such as lithium aluminumhydride, diborane and sodium bis(2-methoxyethoxy) aluminum hydride andthe like per mole of the indazole-3-carboxamide derivatives. Thereaction may be carried out at a temperature between the freezing pointand the boiling point of the solvent, preferably between roomtemperature and the boiling point of the solvent. Any solvent which isinactive in the reaction can be used, which include ethers such astetrahydrofuran, diethyl ether, dioxane and the like; chloroform;methylene chloride; benzene and toluene.

Amine derivatives of formula (VII) ##STR42## wherein m is 0-2, R₃ is aC₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzyl group, of which aphenyl ring may be mono- or di-substituted by the same or differenthalogen atom or methoxy group, can be prepared by the processes shown inthe following Scheme 2. ##STR43## R₄ represents an alkyl group, anarylalkyl group or an aryl group. wherein R₄ represents an alkyl group,an arylalkyl group and an aryl group.

Amine derivatives of formula (VIII) ##STR44## wherein n is 2 or 3, R₃ isa C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzyl group, of whicha phenyl ring may be mono- or di-substituted by the same or differenthalogen atom or methoxy group, can be prepared by the processes shown inthe following Scheme 3. ##STR45##

Amine derivatives of formula (IX) ##STR46## wherein o is 1 or 2, R₃ is aC₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzyl group, of which aphenyl ring may be mono- or di-substituted by the same or differenthalogen atom or methoxy group, can be prepared by the processes shown inthe following Scheme 4. ##STR47##

Amine derivatives of formula (X) ##STR48## wherein p is 2-4, R₃ is a C₁-C₆ alkyl group, a C₃ -C₆ alkenyl group or a benzyl group, of which aphenyl ring may be mono- or di-substituted by the same or differenthalogen atom or methoxy group, can be prepared by the processes shown inthe following Scheme 5. ##STR49##

Examples of the thus prepared compounds of the present invention includethe following:

N-(4-piperidyl)-1-propylindazole-3-carboxamide,

N-(1-methyl-4-piperidyl)-1-propylindazole-3-carboxamide,

N-(1-butyl-4-piperidyl)-1-propylindazole-3-carboxamide,

N-(1-benzyl-4-piperidyl)-1-propylindazole-3-carboxamide,

N-(4-piperidyl)methyl-1-propylindazole-3-carboxamide,

N-(1-methyl-4-piperidyl)methyl-1-propylindazole-3-carboxamide,

N-(1-butyl-4-piperidyl)methyl-1-propylindazole-3-carboxamide,

N- 2-(1-methyl-4-piperidyl)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(1-butyl-4-piperidyl)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(4-methyl-1-piperazinyl)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(4-butyl-1-piperazinyl)ethyl!-1-prcpylindazole-3-carboxamide,

N- 2-(4-butyl-1-piperazinyl)ethyl!-1-sec-butylindazole-3-carboxamide,

N- 2-(4-butyl-1-piperazinyl)ethyl!-1-(3-pentyl)indazole-3-carboxamide,

N- 2-(4-p-fluorobenzyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide,

N-2-(4-p-fluorobenzyl-1-piperazinyl)ethyl!-1-propylindazole-3-carboxamide,

N-2-(4-p-fluorobenzyl-1-piperazinyl)ethyl!-1-allylindazole-3-carboxamide,

N- 3-(4-butyl-1-piperazinyl)propyl!-1-proptindazole-3-carboxamide,

N- 2-(1-methyl-4-piperidylidene)ethyl!-1-propylindazole-3-carboxamide,

N- 2-(1-butyl-4-piperidylidene)ethyl!-1-propylindazole-3-carboxamide,

N-2-(1-p-fluorobenzyl-4-piperidvlidene)ethyl!-1H-indazole-3-carboxamide,

N-2-(1-p-fluorobenzyl-4-piperidylidene)ethyl!-1-propylindazole-3-carboxamide,

N-(1-butyl-4-hexahydroazepinyl)-1-propylindazole-3-carboxamide,

N-(1-butyl-5-octahydroazocinyl)-1-propylindazole-3-carboxamide,

N-(1-butyl-5-octahydroazoninyl)-1-propylindazole-3-carboxamide,

N- 2-(4-allyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide,

N- 2-(4-n-propyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide,

N- 2-(4-n-pentyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide,

N-2-(4-p-methoxybenzyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide,

N- 2-(4-n-butyl-1-piperazinyl)ethyl!-1-ethylindazole-3-carboxamide,

N- 2-(4-n-butyl-1-piperazinyl)ethyl!-1-isopropylindazole-3-carboxamide,

N-2-(4-n-butyl-1-piperazinyl)ethyl!-1-cyclopentylindazole-3-carboxamide,

N-2-(4-n-butyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-thiocarboxamide,

3-{N- 2-(4-n-butyl-1-piperazinyl)ethyl!aminomethyl}-1-n-propylindazoleand the like.

The above compounds of the invention possess potent digestive tractprokinetic action via 5-HT₄ receptors as shown in the followingExamples, and are useful as a therapeutic agent for digestive tractdiseases.

The compounds of formula (I) may be converted, if desired, to thecorresponding acid addition salts with pharmaceutically acceptableacids, and the acid addition salts are included within the scope of thisinvention. They include, for examples, the salts with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid and the like, or the salts with organic acids such as acetic acid,succinic acid, oxalic acid, malic acid, tartaric acid, fumaric acid,maleic acid, citric acid, malonic acid, lactic acid, methanesulfonicacid, p-toluenesulfonic acid, mandelic acid, suberic acid or the like.

The compounds of formula (I) can be formulated into the pharmaceuticalpreparations in various dosage forms. The preparations can beadministered orally in the form of tablets, sugar-coated tablets, hardcapsules, soft capsules and the liquid such as solutions, emulsions andsuspensions. They are administered parenterally in the form ofinjections.

These preparations can be prepared by conventional methods employingconventional additives such as excipients, stabilizers, preservatives,solubilizers, wetting agents, emulsifiers, lubricants, sweeteningagents, colorants, flavorings, isotonicity, buffers, antioxidants or thelike.

Route and dosage for the administration of the present compounds are notspecifically limited and are appropriately chosen depending upon theform of the pharmaceutical preparations, sex of the patient, severity ofthe disease and the like. Daily dosage of the active ingredient is 1 to2000 mg. No adverse toxicological effects are indicated at any of theabove dosage ranges.

This invention will be more fully illustrated by way of the followingPreparation Examples with respect to the preparation of theintermediates of the present compounds, Examples with respect to thepreparation of the present compounds and their pharmacological effects,and Pharmaceutical Examples with respect to the pharmaceuticalpreparation which comprises as an active ingredient the presentcompound. However, it is to be understood that the invention is notintended to be limited to the specific embodiments.

PREPARATION EXAMPLE 1 1-n-Butylpiperazine ##STR50##

Anhydrous piperazine (19.5 g) was dissolved in ethanol (100 ml), and asolution of 1-bromobutane (24.8 g) in ethanol (50 ml) was added dropwiseover a period of 20 minutes at room temperature. After stirringovernight, the reaction solution was filtered off with Celite, and thesolvent was distilled off under reduced pressure. To the residueobtained was added a 40% aqueous solution of sodium hydroxide, andextracted with ether three times. The ether layer was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (methylene chloride:methanol:aqueous ammonia=90:10:0.5)to give the title compound (7.53 g) as a yellow oily substance.Yield=29%.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.27-1.36(m, 2H), 1.43-1.51(m,2H), 2.01(bs, 1H), 2.31(t, J=8 Hz, 2H), 2.20-2.60(m, 4H), 2.90(t, J=5Hz, 4H)

PREPARATION EXAMPLE 2 N- 3-(4-n-Butyl-1-piperazinyl)propyl!phthalimide##STR51##

N-(3-Bromopropyl)phthalimide (15.1 g) was dissolved in acetonitrile (100ml), and 1-n-butylpiperazine (5.33 g) obtained in Preparation Example 1and 50% potassium fluoride-Celite (21.8 g) were added at roomtemperature. After stirring overnight, the reaction solution wasfiltered off with Celite, and the solvent was distilled off underreduced pressure. The residue obtained was purified by silica gel columnchromatography (methylene chloride:methanol=95:5) to give the titlecompound (9.83 g) as a yellow oily substance. Yield=80%.

¹ H NMR(CDCl₃) δ 0.89(t, J=7 Hz, 3H), 1.23-1.33(m, 2H), 1.38-1.46(m,2H), 1.82-1.89(m, 2H), 2.00-2.70(m, 8H), 2.24(t, J=8 Hz, 2H), 2.42(t,J=7 Hz, 2H), 3.76(t, J=7 Hz, 2H), 7.70-7.73(m, 2H), 7.82-7.85(m, 2H)

PREPARATION EXAMPLE 3 N- 2-(4-Methyl-1-piperazinyl)ethyl!phthalimide##STR52##

The title compound was synthesized by using N-(2-bromoethyl)phthalimideand 1-methylpiperazine according to the same process as in PreparationExample 2.

¹ H NMR(CDCl₃) δ 2.26(s, 3H), 2.10-2.80(m, 8H), 2.64(t, J=7 Hz,2H),3.81(t, J=7 Hz, 2H), 7.70-7.73(m, 2H), 7.82-7.85(m, 2H)

PREPARATION EXAMPLE 4 2-(4-n-Butyl-1-piperazinyl)ethanol ##STR53##

2-(1-Piperazinyl)ethanol (12.2 g) was dissolved in chloroform (60 ml),triethylamine (13.0 ml) and 1-bromobutane (14.1 g) were successivelyadded at room temperature, and the mixture was stirred overnight. Thereaction solution was successively washed with a 10 M aqueous solutionof potassium hydroxide (15 ml), water (50 ml×2), saturated aqueoussodium chloride (50 ml), dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue obtainedwas purified by silica gel column chromatography (methylenechloride:methanol:aqueous ammonia=90:10:0.5) to give the title compound(10.8 g) as a pale yellow oily substance. Yield=62%.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.27-1.36(m, 2H), 1.43-1.51(m,2H), 2.31-2.34(m, 2H), 2.30-2.60(m, 8H), 2.54(t, J=5 Hz,2H), 3.60(t, J=5Hz, 2H)

PREPARATION EXAMPLE 5 2-(4-p-Fluorobenzyl-1-piperazinyl)ethanol##STR54##

The title compound was synthesized by using 2-(1-piperazinyl)ethanol andp-fluorobenzyl chloride according to the same process as in PreparationExample 4.

¹ H NMR(CDC₁ ₃) δ 2.20-2.70(m, 8H), 2.54(t, J=5 Hz, 2H), 3.47(s, 2H),3.60(t, J=5 Hz, 2H), 7.00(dd, J=8 Hz, 9 Hz, 2H), 7.28(dd, J=5 Hz, 9 Hz,2H)

PREPARATION EXAMPLE 6 8-p-Fluorobenzyl-1,4-dioxa-8-azaspiro 4.5!decane##STR55##

1,4-Dioxa-8-azaspiro 4.5!decane (29.9 g) was dissolved in chloroform(150 ml), triethylamine (32 ml) and p-fluorobenzyl chloride (27.5 ml)were successively added under ice-cooling, and the mixture was stirredovernight. The reaction solution was successively washed with a 20%aqueous solution of sodium hydroxide (150 ml×2) and water (150 ml),dried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue obtained was purified by silicagel column chromatography (chloroform:methanol=10:1) to give the titlecompound (49.4g) as a yellow oily substance. Yield=94%.

¹ H NMR(CDC₁ ₃) δ 1.73(t, J=5 Hz, 4H), 2.50(bt, J=5 Hz, 4H), 3.48(s,2H), 3.94(s, 4H), 6.96-7.01(m, 2H), 7.25-7.29(m, 2H)

PREPARATION EXAMPLE 7 1-p-Fluorobenzyl-4-piperidone ##STR56##

8-p-Fluorobenzyl-1,4-dioxa-8-azaspiro 4.5!decane (20.7 g) obtained inPreparation Example 6 was dissolved in 5N hydrochloric acid (200 ml),and the mixture was heated under reflux for 23 hours. The reactionsolution was washed with chloroform (100 ml×3), made basic withpotassium carbonate, and extracted with chloroform (100 ml×2,200 ml×1).The chloroform layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to give the crude titlecompound (14.6 g) as a oily substance. Yield=85%. This compound was usedfor the subsequent reaction without purification.

¹ H NMR(CDC₁ ₃) δ 2.45(t, J=6 Hz, 4H), 2.73(t, J=6 Hz, 4H), 3.58(s, 2H),6.98-7.05(m, 2H), 7.28-7.34(m, 2H)

PREPARATION EXAMPLE 8 1-n-Butyl-4-piperidone ##STR57##

To a suspension of 4-piperidone hydrochloride monohydrate (20.6 g) andn-butylamine (25.0 g) in methylene chloride (300 ml) was addedtriethylamine (63 ml), and the mixture was stirred at room temperaturefor 12 hours. Methanol was further added to the reaction solution, andthe solution was made uniform. To the solution were added water (7 ml)and anhydrous potassium carbonate (21.1 g), and the mixture was stirredfor 30 minutes. The reaction solution was filtered off with Celite, andthen the solvent was distilled off under reduced pressure. The residueobtained was purified by silica gel column chromatography(chloroform:methanol=10:1) to give the title compound (13.0 g) as ayellow oily substance. Yield=62%.

¹ H NMR(CDC₁ ₃) δ 0.94(t, J=7 Hz, 3H), 1.36(sext, J=7 Hz, 2H),1.47-1.53(m, 2H), 2.45(t, J=7 Hz, 2H), 2.46(t, J=6 Hz, 4H), 2.74(t, J=6Hz, 4H)

PREPARATION EXAMPLE 9 Ethyl 1-p-fluorobenzyl-4-piperidylideneacetate##STR58##

60% sodium hydride (0.87 g) was suspended in THF (30 ml), and ethyldiethylphosphonoacetate (5.5 ml) was added dropwise under ice-cooling.Then 1-p-fluorobenzyl-4-piperidone (3.76 g) obtained in PreparationExample 7 was added under ice-cooling, and the mixture was stirred for 3hours. The reaction solution was poured into saturated aqueous sodiumchloride (50 ml), and extracted with ethyl acetate (200 ml). The ethylacetate layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue obtainedwas purified by silica gel column chromatography (ethylacetate:hexane=1:4-2:3) to give the title compound (4.57 g) as acolorless oily substance. Yield=91%.

¹ H NMR(CDCl₃) δ 1.27(t, J=7 Hz, 3H), 2.31(t, J=6 Hz, 2H), 2.49(t, J=5Hz, 4H), 2.97(t, J=6 Hz, 2H), 3.47(s, 2H), 4.14(q, J=7 Hz, 2H), 5.63(s,1H), 6.98-7.02(m, 2H), 7.26-7.30(m, 2H)

PREPARATION EXAMPLE 10 Ethyl 1-methyl-4-piperidylideneacetate ##STR59##

The title compound was synthesized by using 1-methyl-4-piperidoneaccording to the same process as in Preparation Example 9.

¹ H NMR(CDCl₃) δ 1.27(t, J=7 Hz, 3H), 2.29(s, 3H), 2.34(t, J=6 Hz, 2H),2.45-2.50(m, 4H), 3.00(t, J=5 Hz, 2H), 4.14(q, J=7 Hz, 2H), 5.65(s, 1H)

PREPARATION EXAMPLE 11 Ethyl 1-n-butyl-4-piperidylideneacetate ##STR60##

The title compound was synthesized by using 1-n-butyl-4-piperidoneobtained in Preparation Example 8 according to the same process as inPreparation Example 9.

¹ H NMR(CDCl₃) δ 0.92(t, J=7 Hz, 3H), 1.27(t, J=7 Hz, 3H), 1.29-1.35(m,2H), 1.48(sept, J=8 Hz, 2H), 2.31-2.35(m, 4H), 2.50(td, J=6 Hz, 9 Hz,4H), 2.99(t, J=6 Hz, 2H), 4.14(q, J=7 Hz, 2H), 5.63(s,1H)

PREPARATION EXAMPLE 12 2-(1-p-Fluorobenzyl-4-piperidylidene)ethanol##STR61##

Ethyl 1-p-fluorobenzyl-4-piperidylideneacetate (2.97 g) obtained inPreparation Example 9 was dissolved in THF (30 ml), to which aluminumdiisobutyl hydride (1.5M toluene solution, 18 ml) was added dropwiseunder ice-cooling, and the mixture was stirred for one hour. To thereaction solution were added aqueous ammonia (10 ml), a 10% aqueoussolution of sodium hydroxide (20 ml) and Celite, and the mixture wasstirred overnight at room temperature. The reaction solution wasfiltered off, extracted with chloroform (200 ml). The chloroform layerwas washed with saturated aqueous sodium chloride (50 ml), dried overanhydrous magnesium sulfate, and the solvent was then distilled offunder reduced pressure to give the title compound (2.57 g) as a paleyellow oily substance. This compound was used for the subsequentreaction without purification.

¹ H NMR(CDCl₃) δ 2.23(t, J=5 Hz, 2H), 2.30(t, J=6 Hz, 2H), 2.40-2.45(m,4H), 3.46(s, 2H), 4.13(d, J=7 Hz, 2H), 5.41(t, J=7 Hz, 1H), 6.97-7.01(m,2H), 7.26-7.29(m, 2H)

PREPARATION EXAMPLE 13 2-(1-Methyl-4-piperidylidene)ethanol ##STR62##

The title compound was synthesized by using ethyl1-methyl-4-piperidylideneacetate obtained in Preparation Example 10according to the same process as in Preparation Example 12.

¹ H NMR(CDCl₃) δ 2.26(t, J=6 Hz, 2H), 2.33(t, J=6 Hz, 2H), 2.38-2.43(m,4H), 4.14(d, J=7 Hz, 2H), 5.42(t, J=7 Hz, 1H)

PREPARATION EXAMPLE 14 2-(1-Methyl-4-piperidyl)ethanol ##STR63##

To a solution of 2-(1-methyl-4-piperidylidene)-ethanol (4.50 g) obtainedin Preparation Example 13 in ethanol (50 ml) was added platinum (IV)oxide (0.10 g), and the mixture was shaken at room temperature underhydrogen atmosphere at 2.1 kg cm² for 5 hours. The reaction solution wasfiltered off with Celite, and the solvent was distilled off underreduced pressure to give the title compound (4.73 g). This compound wasused for the subsequent reaction without purification.

¹ H NMR(CDCl₃) δ 1.23-1.33(m, 2H), 1.36-1,46(m, 1H), 1.52(q, J=7 Hz,2H), 1.69(d, J=13 Hz, 2H), 1.91(dt, J=2 Hz, 12 Hz, 2H), 2.18(s, 1H),2.25(s, 3H), 2.83(d, J=12 Hz, 2H), 3.68(t, J=7 Hz, 2H)

PREPARATION EXAMPLE 15 2-(1-n-Butyl-4-piperidylidene)ethanol ##STR64##

The title compound was synthesized by using ethyl1-n-butyl-4-piperidylideneacetate obtained in Preparation Example 11according to the same process as in Preparation Example 12.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.25-1.36(m, 2H), 1.44-1.52(m,2H), 2.25(t, J=6 Hz, 2H), 2.30-2.37(m, 4H), 2.42-2.47(m,4H), 4.14(d, J=7Hz, 2H), 5.41(t, J=7 Hz, 1H)

PREPARATION EXAMPLE 16 2-(1-n-Butyl-4-piperidyl)ethanol ##STR65##

A suspension of lithium aluminum hydride (0.96 g) in THF (90 ml) wasice-cooled, to which was added dropwise a solution of ethyl1-n-butyl-4-piperidylideneacetate (3.40 g) obtained in PreparationExample 11 in THF (60 ml) over a period of 10 minutes with stirring. Themixture was stirred under ice-cooling for 10 minutes, and then at roomtemperature for further 2 hours. To the reaction solution weresuccessively added water (4 ml), a 15% aqueous solution of sodiumhydroxide (4 ml), water (12 ml), and anhydrous magnesium sulfate, andthe mixture was stirred at room temperature for 30 minutes. The reactionsolution was filtered off with Celite, and the solvent was distilled offunder reduced pressure. To a solution of the residue in ethanol (150 ml)was added platinum (IV) oxide (0.50 g), and the mixture was shaken atroom temperature under hydrogen atmosphere at 2 kg/cm² for 11 hours. Thereaction solution was filtered off with Celite, and the solvent wasdistilled off under reduced pressure to give the title compound (2.76 g)as a yellow oily substance. This compound was used for the subsequentreaction without purification.

PREPARATION EXAMPLE 17 (1-Methyl-1,2,5,6-tetrahydro-4-pyridyl)methanol##STR66##

4-Pyridylmethanol (25.0 g) and methyl iodide (16 ml) were reacted at120° C. in a sealed tube for 3 hours. The quaternary ammonium saltobtained was dissolved in 10% aqueous methanol (300 ml), and thesolution was cooled to -78° C. Sodium borohydride (42.0 g) was addedover a period of 2 hours with stirring. After completion of thereaction, the solvent was distilled off under reduced pressure. To theresidue was added a 20% aqueous solution of sodium hydroxide, andextracted with chloroform. The chloroform layer was washed withsaturated aqueous sodium chloride, dried over anhydrous potassiumcarbonate, and the solvent was distilled off under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia=90:10:1) to give the title compound(17.58 g) as a yellow oily substance. Yield=60%.

¹ H NMR(CDCl₃) δ 2.14(s, 2H), 2.33(t, J=1 Hz, 3H), 2.58(dt, J=1 Hz, 6Hz, 2H), 2.92(s, 2H), 3.95(s, 2H), 4.49(bs, 1H), 5.58(t, J=2 Hz, 1H)

PREPARATION EXAMPLE 18 (1-Methyl-4-piperidyl)methanol ##STR67##

To a solution of (1-methyl-1,2,5,6-tetrahydro-4-pyridyl)methanol (17.6g) obtained in Preparation Example 17 in ethanol (200 ml) was addedplatinum (IV) oxide (0.40 g), and the mixture was shaken at roomtemperature under hydrogen atmosphere at 2 kg/cm² for 5 hours. Thereaction solution was filtered off with Celite, and the solvent was-distilled off under reduced pressure. The residue was purified byvacuum distillation to give the title compound (14.2g). Yield 80%.

b.p. 82-86:° C. (3 mmHg)¹ H NMR(CDCl₃) δ 1.22-1.38(m, 2H), 1.42-1.47(m,1H), 1.75(bd, J=13 Hz, 2H), 1.93(bt, J=11 Hz, 2H), 2.26(s, 3H), 2.87(d,J=11 Hz, 2H), 3.46(dd, J=6 Hz, 11 Hz, 2H)

PREPARATION EXAMPLE 19 Ethyl 1-n-butylisonipecotate and1-n-butylisonipecotic acid ##STR68##

Ethyl isonipecotate (24.0 g) was dissolved in ethanol (200 ml),triethylamine (23 ml) and 1-bromobutane (18 ml) were added in turn atroom temperature, and the mixture was stirred for 24 hours. Water (10ml) and anhydrous potassium carbonate (30 g) were further added, and themixture was stirred for 10 minutes. The reaction solution was filteredoff with Celite, and the solvent was distilled off under reducedpressure. The residue was washed with saturated aqueous sodium chloride,then dried over anhydrous magnesium sulfate and the solvent wasdistilled off under reduced pressure. The residue was purified by vacuumdistillation to give a mixture (16.9 g) of the title compounds.Yield=53%.

b.p. 110-115° C. (9 mmHg)

PREPARATION EXAMPLE 20 (1-n-Butyl-4-piperidyl)methanol ##STR69##

A suspension of lithium aluminum hydride (1.39 g) in THF (100 ml) wasice-cooled, to which was added dropwise a solution of a mixture (4.15 g)of ethyl 1-n-butylisonipecotate and 1-n-butylisonipecotic acid obtainedin Preparation Example 19 in THF (100 ml) over a period of 15 minuteswith stirring. The mixture was stirred under ice-cooling for 10 minutes,and then at room temperature for 30 minutes. To the reaction solutionwere successively added water (2 ml), a 15% aqueous solution of sodiumhydroxide (2 ml), water (6 ml) and anhydrous magnesium sulfate, and themixture was stirred at room temperature for 30 minutes. The reactionsolution was filtered off with Celite, and the solvent was distilled offunder reduced pressure to give the title compound (3.84 g). Thiscompound was used for the subsequent reaction without purification.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.30(sext, J=7 Hz, 2H),1.37-1.54(m, 5H), 1.87(dt, J=2 Hz, 12 Hz, 2H), 2.29(t, J=8 Hz, 2H),2.91(d, J=12 Hz, 2H), 3.68(dt, J=2 Hz, 6 Hz, 2H)

PREPARATION EXAMPLE 21 N- 2-(4-n-Butyl-1-piperazinyl)ethyl!phthalimide##STR70##

2-(4-n-Butyl-1-piperazinyl)ethanol (5.46 g) obtained in PreparationExample 4, triphenylphosphine (8.46 g) and phthalimide (4.74 g) weredissolved in THF (50 ml), and diisopropylazodicarboxylate (6.52 g) wasadded dropwise at room temperature. After stirring overnight, thereaction solution was distilled off under reduced pressure. The residueobtained was purified by silica gel column chromatography (methylenechloride:ethyl acetate=1:1) to give the title compound (6.64 g). Yield72%.

¹ H NMR(CDCl₃) δ 0.88(t, J=7 Hz, 3H), 1.25 1.31(m, 2H), 1.40-1.45(m,2H), 2.20-2.80(m, 8H), 2.28(t, J=8 Hz, 2H), 2.62(t, J=7 Hz, 2H), 3.80(t,J=7 Hz, 2H), 7.68-7.71(m, 2H), 7.80-7.84(m, 2H)

PREPARATION EXAMPLE 22 N-2-(4-p-Fluorobenzyl-1-piperazinyl)ethyl!phthalimide ##STR71##

The title compound was synthesized by using2-(4-p-fluorobenzyl-1-piperazinyl)ethanol obtained in PreparationExample 5 according to the same process as in Preparation Example 21.

¹ H NMR(CDCl₃) δ 2.30-2.70(m, 8H), 2.63(t, J=7 Hz, 2H), 3.43(s, 2H),3.81(t, J=7 Hz, 2H), 7.00(dd, J=8 Hz, 9 Hz, 2H), 7.25(dd, J=5 Hz, 9 Hz,2H), 7.71(dd, J=3 Hz, 5 Hz, 2H), 7.84(dd, J=3 Hz, 9 Hz, 2H)

PREPARATION EXAMPLE 23 N- 2-(1-Methyl-4-piperidylidene)ethyl!phthalimide##STR72##

The title compound was synthesized by using2-(1-methyl-4-piperidylidene)ethanol obtained in Preparation Example 13according to the same process as in Preparation Example 21.

¹ H NMR(CDCl₃) δ 2.23(t, J=6 Hz, 2H), 2.30(s, 3H), 2.41(t, J=6 Hz, 2H),2.48(t, J=5 Hz, 2H), 2.54(t, J=5 Hz, 2H), 4.27(d, J=7 Hz,2H), 5.30(t,J=7 Hz, 1H), 7.69-7.73(m, 2H), 7.82-7.85(m, 2H)

PREPARATION EXAMPLE 24 N-2-(1-n-Butyl-4-piperidylidene)ethyl!phthalimide ##STR73##

The title compound was synthesized by using2-(1-n-butyl-4-piperidylidene)ethanol obtained in Preparation Example 15according to the same process as in Preparation Example 21.

¹ H NMR(CDCl₃) δ 0.91(t, J=8 Hz, 3H), 1.25-136(m, 2H), 1.47-1.55(m, 2H),2.18-2.30(m, 2H), 2.30-2.44(m, 2H), 2.44-2.45(m,2H), 2.54-2.65(m, 2H),4.27(d, J=7 Hz, 2H), 5.29(t, J=7 Hz, 1H), 7.69-7.72(m, 2H), 7.82-7.84(m,2H)

PREPARATION EXAMPLE 25 N-2-(1-p-Fluorobenzyl-4-piperidylidene)ethyl!phthalimide ##STR74##

The title compound was synthesized by using2-(1-p-fluorobenzyl-4-piperidylidene)ethanol obtained in PreparationExample 12 according to the same process as in Preparation Example 21.

¹ H NMR(CDCl₃) δ 2.18(t, J=5 Hz, 2H), 2.39(t, J=6 Hz, 2H), 2.48(bs, 4H),3.46(s, 2H), 4.26(d, J=7 Hz, 2H), 5.28(t, J=7 Hz, 1H), 6.99(t, J=8 Hz,2H), 7.27(dd, J=5 Hz, 8 Hz, 2H), 7.70(dd, J=3 Hz, 5 Hz, 2H), 7.83(dd,J=3 Hz, 5 Hz, 2H)

PREPARATION EXAMPLE 26 N-(1-Methyl-4-piperidyl)methylphthalimide##STR75##

(1-Methyl-4-piperidyl)methanol (4.00 g) obtained in Preparation Example18, triphenylphosphine (9.00 g) and phthalimide (5.04 g) were suspendedin THF (40 ml), to which diethyl azocarboxylate (6.7 ml) was addeddropwise at room temperature, and the mixture was stirred for 12 hours.The reaction solution was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (methanol:ethylacetate=1:10-methanol:chloroform=1:5) to give the title compound (6.34g). Yield=79%.

¹ H NMR(CDCl₃) δ 1.34-1.44(m, 2H), 1.67(d, J=13 Hz, 2H), 1.68-1.84(m,1H), 1.87(dt, J=1 Hz, 12 Hz, 2H), 2.24(s. 3H), 2.83(d, J=12 Hz, 2H),7.23-7.28(m, 2H), 7.83-7.85(m, 2H)

PREPARATION EXAMPLE 27 N-(1-n-Butyl-4-piperidyl)methylphthalimide##STR76##

The title compound was synthesized by using(1-n-butyl-4-piperidyl)methanol obtained in Preparation Example 20according to the same process as in Preparation Example 26.

¹ H NMR(CDCl₃) δ 0.90(t, J=7 Hz, 3H), 1.29(sept, J=7 Hz, 2H),1.35-1.44(m, 2H), 1.45(sept, J=8 Hz, 2H), 1.66(d, J=13 Hz, 2H),1.74-1.82(m, 1H), 1.87(t, J=11 Hz, 2H), 2.29(t, J=8 Hz, 2H), 2.90(d,J=11 Hz, 2H), 3.60(d, J=7 Hz, 2H), 7.70-7.72(m, 2H), 7.83-7.85(m, 2H)

PREPARATION EXAMPLE 28 N- 2-(1-Methyl-4-piperidyl)ethyl!phthalimide##STR77##

The title compound was synthesized by using2-(1-methyl-4-piperidyl)ethanol obtained in Preparation Example 14according to the same process as in Preparation Example 26.

¹ H NMR(CDCl₃) δ 1.22-1.38(m, 3H), 1.62(q, J=7 Hz, 2H), 1.79(d,J=11 Hz,2H), 1.91(dd, J=10 Hz, 11 Hz, 2H), 2.26(s, 3H), 2.87(d, J=11 Hz, 2H),3.72(t, J=7 Hz, 2H), 7.71(d, J=5 Hz, 2H), 7.84(d, J=5 Hz,2H)

PREPARATION EXAMPLE 29 N- 2-(1-n-Butyl-4-piperidyl)ethyl!phthalimide##STR78##

The title compound was synthesized by using2-(1-n-butyl-4-piperidyl)ethanol obtained in Preparation Example 16according to the same process as in Preparation Example 26.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.25-1.35(m, 5H), 1.48(sept, J=7Hz, 2H), 1.62(q, J=6 Hz, 2H), 1.78(d, J=10 Hz, 2H), 1.89(t, J=10 Hz,2H), 2.30(t, J=8 Hz, 2H), 2.93(d, J=11 Hz, 2H), 3.72(t,J=7 Hz, 2H),7.70-7.72(m, 2H), 7.83-7.85(m, 2H)

PREPARATION EXAMPLE 30 3-(4-n-Butyl-1-piperazinyl)propylamine ##STR79##

N- 3-(4-n-Butyl-1-piperazinyl)propyl!phthalimide (8.18 g) obtained inPreparation Example 2 was dissolved in methanol (80 ml), hydrazinemonohydrate (1.86 g) was added at room temperature, and the mixture washeated under reflux for 2 hours. After completion of the reaction, thereaction solution was cooled to room temperature, and aqueous ammonia(40 ml) was added. After stirring for 15 minutes, the reaction solutionwas filtered off with Celite, and the solvent was distilled off underreduced pressure. To the residue were added chloroform (100 ml) andanhydrous potassium carbonate, and the solution was shaken at 40° C. for15 minutes. The reaction solution was filtered off with Celite, and thesolvent was distilled off under reduced pressure. The residue waspurified by vacuum distillation to give the title compound (3.96 g) as apale yellow oily substance. Yield=80%.

b.p. 132-133° C. (7 mmHg)

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.26-1.36(m, 2H), 1.43-1.50(m,2H), 1.60-1.67(m, 2H), 2.30-2.34(m, 2H), 2.40(t, J=8 Hz, 2H),2.30-2.70(m, 8H), 2.74(t, J=7 Hz, 2H)

PREPARATION EXAMPLE 31 2-(4-Methyl-1-piperazinyl)ethylamine ##STR80##

The title compound was synthesized by using N-2-(4-methyl-1-piperazinyl)ethyl!phthalimide obtained in PreparationExample 3 according to the same process as in Preparation Example 30.

¹ H NMR(CDCl₃) δ 2.28(s, 3H), 2.20-2.70(m, 8H), 2.42(t, J=6 Hz,2H),2.78(t, J=6 Hz, 2H)

PREPARATION EXAMPLE 32 2-(4-n-Butyl-1-piperazinyl)ethylamine ##STR81##

The title compound was synthesized by using N-2-(4-n-butyl-1-piperazinyl)ethyl!phthalimide obtained in PreparationExample 21 according to the same process as in Preparation Example 30.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.29-1.34(m, 2H), 1.43-1.51(m,2H), 2.32(t, J=4 Hz, 2H), 2.30-2.60(m, 8H), 2.42(t, J=6 Hz, 2H), 2.77(t,J=6 Hz, 2H)

PREPARATION EXAMPLE 33 2-(4-p-Fluorobenzyl-1-piperazinyl)ethylamine##STR82##

The title compound was synthesized by using N-2-(4-p-fluorobenzyl-1-piperazinyl)ethyl!phthalimide obtained inPreparation Example 22 according to the same process as in PreparationExample 30.

¹ H NMR(CDCl₃) δ 2.10-2.70(m, 8H), 2.42(t, J=6 Hz, 2H), 2.78(t,J=6 Hz,2H), 3.47(s, 2H), 6.99(t, J=9 Hz, 2H), 7.27(dd, J=6 Hz, 9 Hz,2H)

PREPARATION EXAMPLE 34 2-(1-Methyl-4-piperidylidene)ethylamine ##STR83##

The title compound was synthesized by using N-2-(1-methyl-4-piperidylidene)ethyl!phthalimide obtained in PreparationExample 23 according to the same process as in Preparation Example 30.

¹ H NMR(CDCl₃) δ 2.22(t, J=6 Hz, 2H), 2.27(s, 3H), 2.29(t, J=6 Hz, 2H),2.36-2.41(m, 4H), 3.27(d, J=7 Hz, 2H), 5.27(t, J=7 Hz, 1H)

PREPARATION EXAMPLE 35 2-(1-n-Butyl-4-piperidylidene)ethylamine##STR84##

The title compound was synthesized by using N-2-(1-n-butyl-4-piperidylidene)ethyl!phthalimide obtained in PreparationExample 24 according to the same process as in Preparation Example 30.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.25-1.36(m, 2H), 1.44-1.52(m,2H), 2.20-2.45(m, 10H), 3.27(d, J=7 Hz, 2H), 5.25(t, J=7 Hz, 1H)

PREPARATION EXAMPLE 36 2-(1-p-Fluorobenzyl-4-piperidylidene)ethylamine##STR85##

The title compound was synthesized by using N-2-(1-p-fluorobenzyl-4-piperidylidene)ethyl!phthalimide obtained inPreparation Example 25 according to the same process as in PreparationExample 30.

¹ H NMR(CDCl₃) δ 1.25(bs, 2H), 2.19(t, J=6 Hz, 2H), 2.26(t J=5 Hz, 2H),2.38-2.43(m, 4H), 3.26(d, J=7 Hz, 2H), 3.46(s, 2H), 5.25(t, J=7 Hz, 1H),6.97-7.01(m, 2H), 7.26-7.29(m, 2H)

PREPARATION EXAMPLE 37 (1-Methyl-4-piperidyl)methylamine ##STR86##

N-(1-Methyl-4-piperidyl)methylphthalimide (5.10 g) obtained inPreparation Example 26 was dissolved in ethanol (100 ml), hydrazinemonohydrate (1.29 g) was added at room temperature, and the mixture washeated under reflux for 6 hours. After completion of the reaction, thereaction solution was cooled to room temperature, a 20% aqueous solutionof sodium hydroxide (20 ml) was added. After stirring for 10 minutes,the reaction solution was distilled off under reduced pressure. To theresidue were added chloroform (80 ml) and anhydrous potassium carbonate(30 g), and the mixture was stirred at 50° C. for 10 minutes. Thereaction solution was filtered off with Celite, and the solvent wasdistilled off under reduced pressure. The residue was purified by vacuumdistillation to give the title compound (1.56 g). Yield=61%.

b.p. 30-50° C. (4 mmHg)

¹ H NMR(CDCl₃) δ 1.28-1.32(m, 2H), 1.42-1.56(m, 1H), 1.77(d, J=13 Hz,2H), 2.03(dt, J=2 Hz,10 Hz, 2H), 2.29(s, 3H), 2.68(d, J=7 Hz, 2H),2.91(d, J=12 Hz, 2H)

PREPARATION EXAMPLE 38 (1-n-Butyl-4-piperidyl)methylamine ##STR87##

N-(1-n-Butyl-4-piperidyl)methylphthalimide (3.62 g) obtained inPreparation Example 27 was dissolved in methanol (100 ml), hydrazinemonohydrate (0.87 g) was added at room temperature, and the mixture wasstirred for 48 hours. The reaction solution was filtered off withCelite, aqueous ammonia (30 ml) was added, and the mixture was stirredfor 10 minutes. Then, the volatiles were distilled off. To the residuewere added chloroform and anhydrous potassium carbonate (25 g), and themixture was shaken at 40° C. for 15 minutes. The reaction solution wasfiltered off with Celite, and the solvent was distilled away underreduced pressure to give the crude title compound (2.39 g) as an oilysubstance. This compound was used for the subsequent reaction withoutpurification.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.22-1.34(m, 5H), 1.48(sept, J=8Hz, 5H), 1.71(d, J=9 Hz, 2H), 1.88(t, J=10 Hz, 2H), 2.30(t, J=8 Hz, 2H),2.56(d, J=6 Hz, 2H), 2.95(d, J=12 Hz, 2H)

PREPARATION EXAMPLE 39 2-(1-Methyl-4-piperidyl)ethylamine ##STR88##

The title compound was synthesized by using N-2-(1-methyl-4-piperidyl)ethyl!phthalimide obtained in PreparationExample 28 according to the same process as in Preparation Example 38.

¹ H NMR(CDCl₃) δ 1.27-1.34(m, 2H), 1.42-1.49(m, 2H), 1.60-1.66(m, 1H),1.72(t, J=13 Hz, 2H), 1.97-2.05(m, 2H), 2.24(d, J=6 Hz, 3H), 2.66(t, J=7Hz, 1H), 2.85(t, J=11 Hz, 2H), 3.30-3.32(m,1H)

PREPARATION EXAMPLE 40 2-(1-n-Butyl-4-piperidyl)ethylamine ##STR89##

The title compound was synthesized by using N-2-(1-n-butyl-4-piperidyl)ethyl!phthalimide obtained in PreparationExample 29 according to the same process as in Preparation Example 38.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.22-1.40(m, 5H), 1.40-1.45(m,2H), 1.45-1.62(m, 2H), 1.66(t, J=12 Hz, 2H), 1.87(t, J=11 Hz, 2H),2.28(t, J=8 Hz, 2H), 2.72(t, J=7 Hz, 1H), 2.91(d, J=12 Hz, 2H),3.43(t,J=7 Hz, 1H)

PREPARATION EXAMPLE 41 Diethyl 5-n-butyl-5-azanonanedioate ##STR90##

To ethyl 4-bromobutylate (25.7 g) was added n-butylamine (5.77 g), andthe mixture was stirred at room temperature. A 10N aqueous solution ofsodium hydroxide (30 ml) was added dropwise, and the mixture was stirredfor 30 minutes. Then ammonium tetrabutyl hydrogensulfate (0.98 g) wasadded, and stirring further continued for one hour. The reactionsolution was extracted with ether (200 ml), successively washed withwater (100 ml) and saturated aqueous sodium chloride (100 ml), and driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced-pressure. The residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:10-1:0-chloroform:methanol=10:1)to give the title compound (10.2 g) as a colorless oily substance.Yield=51%.

¹ H NMR(CDCl₃) δ 0.89(t, J=7 Hz, 3H), 1.25(t, J=7 Hz, 6H), 1.23-1.39(m,4H), 1.69-1.76(m, 4H), 2.29-2.42(m, 10H), 4.12(q, J=7 Hz, 4H)

PREPARATION EXAMPLE 42 1-n-Butyl-5-octahydroazocinone ##STR91##

A suspension of potassium tert-butoxide (11.4 g) in toluene (1000 ml)was heated under reflux for 90 minutes, then a solution of diethyl5-n-butyl-5-azanonanedioate (10.2 g) obtained in Preparation Example 41in toluene (300 ml) was added dropwise over a period of one hour underreflux. The mixture was further heated under reflux for one hour. Thesolvent was distilled off at ordinary pressure, then to the residue wasadded water (400 ml). The mixture was shaken at 50° C. for 30 minutes toobtain a homogeneous solution, then hydrochloric acid (25 ml) was addedthereto, and the mixture was heated under reflux for one hour. After thereaction solution was ice-cooled, the solution was made basic withanhydrous potassium carbonate, and extracted with chloroform (500 ml×3).The chloroform layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (methylenechloride:methanol:aqueous ammonia=90:10:0.5) to give the title compound(1.62 g) as a brown oily substance. Yield=26%.

¹ H NMR(CDCl₃) δ 0.88(t, J=7 Hz, 3H), 1.17-1.26(m, 2H), 1.32-1.40(m,2H), 1.87-1.93(m, 4H), 2.19(t, J=6 Hz, 4H), 2.32(t, J=8 Hz, 2H), 2.49(t,J=6 Hz, 4H)

PREPARATION EXAMPLE 43 1-n-Butyl-5-octahydroazocinone oxime ##STR92##

To a solution of 1-n-butyl-5-octahydroazocinone (1.62 g) obtained inPreparation Example 42 in methanol (20 ml) were successively addedhydroxylamine hydrochloride (3.07 g) and 1,8-diazabicyclo5.4.0!-7-undecane (1.61 g) at room temperature, and the mixture wasstirred overnight. After the reaction solution was distilled off underreduced pressure, the residue was dissolved in water (40 ml), and thesolution was made basic with potassium carbonate, extracted withchloroform (50 ml×3). The chloroform layer was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(methylene chloride:methanol:aqueous ammonia=90:10:0.5) to give thetitle compound (1.60 g) as a pale yellow oily substance. Yield=91%.

¹ H NMR(CDCl₃) δ 0.87(t, J=7 Hz, 3H), 1.22-1.38(m, 4H), 1.71-1.77(m,4H), 2.23-2.26(m, 2H), 2.36-2.51(m, 8H), 7.60-7.68(m, 1H)

PREPARATION EXAMPLE 44 1-n-Butyl-5-octahydroazocinylamine ##STR93##

To a solution of 1-n-butyl-5-octahydroazocinone oxime (1.60 g) obtainedPreparation Example 43 in n-pentyl alcohol (100 ml) was added metallicsodium (about 5 g) under reflux-heating, and the mixture was heatedunder reflux for 2 hours. After completion of the reaction, the mixturewas allowed to cool to room temperature. Then water (150 ml) andhydrochloric acid were added, the reaction solution was made acidic, andwashed with ethyl acetate (150 ml×2). The aqueous layer was made basicwith sodium hydroxide, and extracted with chloroform (100 ml×3). Thechloroform layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to give the titlecompound (1.34 g) as a yellow oily substance. This compound was used forthe subsequent reaction without purification.

¹ H NMR(CDCI₃) δ 0.90(t, J=7 Hz, 3H), 1.26-1.33(m, 2H), 1.35-1.44(m,2H), 1.51-1.62(m, 4H), 1.63-1.74(m, 4H), 2.40(t, J=7 Hz, 2H), 2.45(t,J=6 Hz, 4H), 3.26-3.36(m, 1H)

PREPARATION EXAMPLE 45 1-n-Propylindazole-3-carboxylic acid ##STR94##

To a solution of 1H-indazole-3-carboxylic acid (5.00 g) in DMF (40 ml)was gradually added 60% sodium hydride (1.55 g) at 0° C. with stirring,and the mixture was stirred at room temperature for one hour. Then1-bromopropane (4.55 g) was added, and the mixture was stirredovernight. The reaction solution was distilled off, dissolved in water,and washed with ethyl acetate. The aqueous layer was made acidic withhydrochloric acid, extracted with ethyl acetate, then the extract wasdried over anhydrous magnesium sulfate, and decolorized with activecarbon. After the solvent was distilled off, crystallization from ethergave the title compound (4.24 g) as crystals. Yield=67%.

¹ H NMR(CDCl₃) δ 0.97(t, J=7 Hz, 3H), 2.03(sext, J=7 Hz, 2H), 4.47(t,J=7 Hz, 2H), 7.34-7.53(m, 3H), 8.27(d, J=8 Hz, 1H)

PREPARATION EXAMPLE 46 2-(4-Benzyl-1-piperazinyl)ethanol ##STR95##

The title compound was synthesized by using 2-(1-piperazinyl)ethanol andbenzyl bromide according to the same process as in Preparation Example4.

¹ H NMR(CDCl₃) δ 1.81(bs, 1H), 2.50(bs, 8H), 2.54(t, J=5 Hz, 2H),3.51(s, 2H), 3.60(t, J=5 Hz, 2H), 7.23-7.27(m, 1H), 7.28-7.34(m, 4H )

PREPARATION EXAMPLE 47 N- 2-(4-Benzyl-1-piperazinyl)ethyl!phthalimide##STR96##

The title compound was synthesized by using2-(4-benzyl-1-piperazinyl)ethanol obtained in Preparation Example 46according to the same process as in Preparation Example 26.

¹ H NMR(CDCl₃) δ 2.42(bs, 4H), 2.55(bs, 4H), 2.63(t, J=7 Hz, 2H),3.47(s, 2H), 3.81(t, J=7 Hz, 2H), 7.21-7.30(m, 5H), 7.70-7.72(m, 2H),7.83-7.85(m, 2H

PREPARATION EXAMPLE 48 2-(4-Benzyl-1-piperazinyl)ethylamine ##STR97##

The title compound was synthesized by using N-2-(4-benzyl-1-piperazinyl)ethyl!phthalimide obtained in PreparationExample 47 according to the same process as in Preparation Example 30.

¹ H NMR(CDCl₃) δ 1.51(bs, 2H), 2.39-2.43(m, 6H), 2.47(bs, 4H), 2.77(t,J=6 Hz, 2H), 3.50(s, 2H), 7.22-7.27(m, 1H), 7.28-7.31(m,4H)

EXAMPLE 1 N-3-(4-n-Butyl-1-piperazinyl)propyl!-1-n-propylindazole-3-carboxamide##STR98##

3-(4-n-Butyl-1-piperazinyl)propylamine (0.90 g) obtained in PreparationExample 30 was dissolved in DMF (20 ml), 1-n-propylindazole-3-carboxylicacid (0.92 g) obtained in Preparation Example 45 anddiethylphosphorocyanidate (0.81 g) were successively added, and themixture was stirred overnight. The reaction solution alas diluted withmethylene chloride (200 ml), washed in turn with water (60 ml×3) andsaturated aqueous sodium chloride (60 ml), dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(methylene chloride:methanol=90:10) to give the title compound (1.01 g)as a pale yellow oily substance. Yield=58%.

¹ H NMR(CDCl₃) δ 0.92(t, J=7 Hz, 3H), 0.94(t, J=7 Hz, 3H), 1.30-1.38(m,2H), 1.46-1.53(m, 2H), 1.79-1.85(m, 2H), 1.93-2.02(m, 2H), 2.37(t, J=8Hz, 2H), 2.30-2.80(m, 8H), 2.53(t, J=7 Hz, 2H), 3.59(dt, J=5 Hz, 6 Hz,2H), 7.23-7.27(m, 1H), 7.37-7.42(m, 1H), 7.97(bs, 1H), 8.39(d, J=8 Hz,1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 188-194° C.

EXAMPLE 2 N-2-(4-Methyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide##STR99##

The title compound was synthesized by using2-(4-methyl-1-piperazinyl)ethylamine obtained in Preparation Example 31and 1-n-propylindazole-3-carboxylic acid obtained in Preparation Example45 according to the same process as in Example 1.

¹ H NMR(CDCl₃) δ 0.95(t, J=8 Hz, 3H), 1.96-2.01(m, 2H), 2.30(s, 3H),2.30-2.70(m, 8H), 2.65(t, J=6 Hz, 2H), 3.61(dt, J=5 Hz, 6 Hz, 2H),4.35(t, J=7 Hz, 2H), 7.24-7.28(m, 1H), 7.38-7.41(m, 3H), 8.37(d, J=8 Hz,1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 186-193° C.

EXAMPLE 3 N-2-(4-n-Butyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide##STR100##

The title compound was synthesized by using2-(4-n-butyl-1-piperazinyl)ethylamine obtained in Preparation Example 32and 1-n-propylindazole-3-carboxylic acid obtained in Preparation Example45 according to the same process as in Example 1.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 0.94(t, J=7 Hz, 3H), 1.28-1.34(m,2H), 1.43-1.49(m, 2H), 1.97-2.03(m, 2H), 2.34(t, J=8 Hz, 2H),2.40-2.80(m, 8H), 2.86(t, J=6 Hz, 2H), 4.44(t, J=7 Hz, 2H), 4.57(t, J=6Hz, 2H), 7.29-7.33(m, 1H), 7.42-7.49(m, 2H), 8.24(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 204-207° C.

EXAMPLE 4 N-2-(1-Methyl-4-piperidylidene)ethyl!-1-n-propylindazole-3-carboxamide##STR101##

The title compound was synthesized by using2-(1-methyl-4-piperidylidene)ethylamine obtained in Preparation Example34 and 1-n-propylindazole-3-carboxylic acid obtained in PreparationExample 45 according to the same process as in Example 1.

¹ H NMR(CDCl₃) δ 0.94(t, J=7 Hz, 3H), 1.94-2.02(m, 2H), 2.30(t,J=6 Hz,2H), 2.31(s, 3H), 2.43-2.48(m, 6H), 4.11(d, J=5 Hz, 6 Hz, 2H), 4.34(t,J=7 Hz, 2H), 5.38(t, J=7 Hz, 1H), 6.91-7.00(m, 1H), 7.24-7.28(m, 1H),7.40-7.41(m, 2H), 8.38(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

IR(KBr) 3420, 2962, 2936, 1652, 1538, 1198, 754cm⁻¹

EXAMPLE 5 N-2-(1-n-Butyl-4-piperidylidene)ethyl!-1-n-propylindazole-3-carboxamide##STR102##

The title compound was synthesized by using2-(1-n-butyl-4-piperidylidene)ethylamine obtained in Preparation Example35 and 1-n-propylindazole-3-carboxylic acid obtained in PreparationExample 45 according to the same process as in Example 1.

¹ H NMR(CDCl₃) δ 0.92(t, J=7 Hz, 3H), 0.94(t, J=8 Hz, 3H), 1.28-1.38(m,2H), 1.51-1.59(m, 2H), 1.92-2.02(m, 2H), 2.25-2.39(m, 2H), 2.39-2.52(m,4H), 2.52-2.70(m, 4H), 4.10(t, J=6 Hz, 2H), 4.34(t, J=7 Hz, 2H), 5.38(t,J=7 Hz, 1H), 6.89-7.01(m, 1H), 7.24-7.28(m, 1H), 7.40-7.41(m, 2H),8.38(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 162-167° C.

EXAMPLE 6N-(1-n-Butyl-5-octahydroazocinyl)-1-n-propylindazole-3-carboxamide##STR103##

The title compound was synthesized by using1-n-butyl-5-octahydroazocinylamine obtained in Preparation Example 44and l-n-propylindazole-3-carboxylic acid obtained in Preparation Example45 according to the same process as in Example 1.

¹ H NMR(CDCl₃) δ 0.91-0.96(m, 6H), 1.28-1.40(m, 4H), 1.59-1.83(m, 8H),1.91-2.00(m, 2H), 2.40-2.70(m, 4H), 4.22-4.29(m,2H), 4.32(t, J=7 Hz,2H), 4.68-4.83(m, 1H), 7.22-7.26(m, 1H), 7.35-7.41(m, 2H), 8.41(d, J=8Hz, 1H), 8.52-8.66(m, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

IR(KBr) 2938, 2876, 2822, 1652, 1533, 1492, 1196, 1035, 754 cm⁻¹

EXAMPLE 7N-(1-Methyl-4-piperidyl)methyl-1-n-propylindazole-3-carboxamide##STR104##

The title compound was synthesized by using(1-methyl-4-piperidyl)methylamine obtained in Preparation Example 37 and1-n-propylindazole-3-carboxylic acid obtained in Preparation Example 45according to the same process as in Example 1.

¹ H NMP(CDCl₃) δ 0.95(t, J=7 Hz, 3H), 1.42-1.47(m, 2H), 1.62-1.75(m,1H), 1.95-2.10(m, 4H), 1.97(sext, J=7 Hz, 2H), 1.95-2.10(m, 3H), 2.30(s,3H), 2.91(d, J=12 Hz, 2H), 3.40(t, J=5 Hz, 2H), 4.34(t, J=6 Hz, 2H),7.10-7.15(m, 1H), 7.24-7.28(m, 1H), 7.40-7.41(m, 2H), 8.38(d, J=8 Hz,1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 115-135° C.

EXAMPLE 8 N-2-(1-Methyl-4-piperidyl)ethyl!-1-n-propylindazole-3-carboxamide##STR105##

The title compound was synthesized by using2-(1-methyl-4-piperidyl)ethylamine obtained in Preparation Example 39and 1-n-propylindazole-3-carboxylic acid obtained in Preparation Example45 according to the same process as in Example 1.

¹ H NMR(CDCl₃) δ 0.94(t, J=7 Hz, 3H), 1.25-1.37(m, 3H), 1.62(dd, J=6 Hz,15 Hz, 2H), 1.77(dd, J=1 Hz, 12 Hz, 2H), 1.89-1.98(m, 4H), 2.26(s, 3H),2.84(d, J=12 Hz, 2H), 3.53(q, J=5 Hz, 2H), 4.34(t, J=7 Hz, 2H), 7.25(bs,1H), 7.25-7.28(m, 1H), 7.40-7.41(m, 2H), 8.38(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

EXAMPLE 9 N-2-(1-p-Fluorobenzyl-4-piperidylidene)ethyl!-1H-indazole-3-carboxamide##STR106##

2-(1-p-Fluorobenzyl-4-piperidylidene)ethylamine (0.60 g) obtained inPreparation Example 36 was dissolved in DMF (10 ml), diindazolo 2,3-a!2',3'-d!pyrazine-7,14-dione (0.44 g), N,N-dimethylaminopyridine (0.05 g)and anhydrous potassium carbonate (0.53 g) were successively added, andthe mixture was stirred overnight. The reaction solution was dilutedwith ethyl acetate (150 ml), washed with water (50 ml×3), dried overanhydrous magnesium sulfate, and distilled off under reduced pressure.The residue was purified by silica gel column chromatography (methylenechloride:methanol=90:10) to give the title compound (0.73 g) as a paleyellow oily substance. Yield=75%.

¹ H NMR(CDCl₃) δ 2.24(t, J=5 Hz, 2H), 2.37(t, J=5 Hz, 2H), 2.44(t, J=5Hz, 4H), 3.48(s, 2H), 4.10(dd, J=5 Hz, 6 Hz, 2H), 5.33(t, J=7 Hz, 1H),6.96-7.02(m, 3H), 7.25-7.30(m, 3H), 7.41(dt, J=1 Hz, 8 Hz, 1H), 7.47(d,J=8 Hz, 1H), 8.41(d, J=8 Hz, 1H), 10.82(bs 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 147-152° C.

EXAMPLE 10 N-2-(4-n-Butyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide ##STR107##

The title compound was synthesized by using2-(4-n-butyl-1-piperazinyl)ethylamine obtained in Preparation Example 32and diindazolo 2,3-a! 2',3'-d!pyrazine-7,14-dione according to the sameprocess as in Example 9.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 1.25-1.36(m, 2H), 1.44-1.52(m,2H), 2.35(t, J=8 Hz, 2H), 2.30-2.80(m, 8H), 2.68(t, J=6 Hz, 2H),3.64(dt, J=5 Hz, 6 Hz, 2H), 7.26(t, J=8 Hz, 1H), 7.41(t, J=8 Hz, 1H),7.49(t, J=8 Hz, 1H), 7.63(bs, 1H), 8.36(d, J=8 Hz, 1H), 10.95(bs, 1H)

EXAMPLE 11 N-2-(4-p-Fluorobenzyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide##STR108##

The title compound was synthesized by using2-(4-p-fluorobenzyl-1-piperazinyl)ethylamine obtained in PreparationExample 33 and diindazolo 2,3-a! 2',3'-d!pyrazine-7,14-dione accordingto the same process as in Example 9.

¹ H NMR(CDCl₃) δ 2.51(bs, 4H), 2.63(bs, 4H), 2.71(t, J=6 Hz, 2H),3.46(s, 2H), 3.67(dt, J=5 Hz, 6 Hz, 2H), 6.98(t, J=8 Hz, 2H),7.00-7.26(m, 3H), 7.33-7.37(m, 1H), 7.42(d, J=9 Hz, 1H), 7.81(t,J=5 Hz,1H), 8.29(d, J=8 Hz, 1H), 11.88(bs, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 228-238° C. (dec.)

EXAMPLE 12 N-2-(1-p-Fluorobenzyl-4-piperidylidene)ethyl!-1-n-propylindazole-3-carboxamide##STR109##

N- 2-(1-p-Fluorobenzyl-4-piperidylidene)ethyl!-1H-indazole-3-carboxamide(0.33 g) obtained ln Example 9 was dissolved in DMF (5 ml), 60% sodiumhydride (0.05 g) and 1-bromopropane (0.21 g) were successively addedunder ice-cooling, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate (50ml), washed with water (20 ml×4), dried over anhydrous magnesiumsulfate, and distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:1)to give the title compound (0.15 g). Yield=41%.

¹ H NMR(CDCl₃) δ 0.94(t, J=7 Hz, 3H), 1.92-2.02(m, 2H), 2.24(t,J=5 Hz,2H), 2.38(t, J=5 Hz, 2H), 2.44(bs, 4H), 3.47(s, 2H), 4.08-4.12(m, 2H),4.33(dd, J=7 Hz, 7 Hz, 2H), 5.35(t, J=7 Hz, 1H), 6.90(bs, 1H), 6.99(t,J=9 Hz, 1H), 7.23-7.30(m, 3H), 7.39-7.40(m, 2H), 8.38(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 192-201° C. (dec.) ¹ H NMR(D₂ O) δ 0.84(t, J=8 Hz, 3H),1.89-1.96(m, 2H), 2.30-2.60(m, 1H), 2.54(bs, 2H), 2.80-3.20(m, 3H),3.40-3.80(m, 2H), 4.09(bs, 2H), 4.33(s, 2H), 4.40(t, J=7 Hz, 2H),5.61(t, J=7 Hz, 2H), 7.26(t, J=9 Hz, 2H), 7.37(t, J=8 Hz, 1H),7.51-7.55(m, 3H), 7.65(d, J=8 Hz, 1H), 8.09(d, J=8 Hz, 1H)

EXAMPLE 13 N-2-(4-n-Butyl-1-piperazinyl)ethyl!-1-sec-butylindazole-3-carboxamide##STR110##

The title compound was synthesized by using N-2-(4-n-butyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide obtained inExample 10 and 2-bromobutane according to the same process as in Example12.

¹ H NMR(CDCl₃) δ 0.80(t, J=7 Hz, 3H), 0.92(t, J=7 Hz, 3H), 1.30-1.37(m,2H), 1.45-1.53(m, 2H), 1.59(d, J=7 Hz, 2H), 1.86-1.97(m, 1H),2.05-2.17(m, 1H), 2.36(t, J=8 Hz, 2H), 2.30-2.80(m, 8H), 2.66(t, J=6 Hz,2H), 3.55-3.65(m, 2H), 4.57-4.62(m, 1H), 7.24-7.27(m, 1H), 7.36-7.47(m,3H), 8.37(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 168-172° C. (dec.)

¹ H NMPR(D₂ O) δ 0.75(t, J=7 Hz, 3H), 0.99(t, J=7 Hz, 3H), 1.41-1.50(m,2H), 1.62(d, J=6 Hz, 2H), 1.76-1.83(m, 2H), 1.96-2.12(m,2H), 3.34(t, J=8Hz, 2H), 3.50-4.10(m, 8H), 3.61(t, J=6 Hz, 2H), 3.96(t, J=6 Hz, 2H),4.83-4.87(m, 1H), 7.44(t, J=8 Hz, 1H), 7.59(t, J=8 Hz, 1H), 7.80(t, J=8Hz, 1H), 8.18(t, J=8 Hz, 1H)

EXAMPLE 14 N-2-(4-n-Butyl-1-piperazinyl)ethyl!-1-(3-pentyl)indazole-3-carboxamide##STR111##

The title compound was synthesized by using N-2-(4-n-butyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide obtained inExample 10 and 3-pentyl bromide according to the same process as inExample 12.

¹ H NMR(CDCl₃) δ 0.74(t, J=7 Hz, 6H), 0.92(t, J=7 Hz, 3H), 1.28-1.37(m,2H), 1.45-1.53(m, 2H), 1.88-1.99(m, 2H), 2.04-2.16(m, 2H), 2.35(t, J=8Hz, 2H), 2.40-2.70(m, 8H), 2.66(t, J=7 Hz, 2H), 3.55-3.65(m, 2H),7.23-7.27(m, 1H), 7.36-7.47(m, 3H), 8.38(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 146-149° C.

¹ H NMR(D₂ O) δ 0.71(t, J=8 Hz, 6H), 0.99(t, J=7 Hz, 3H), 1.42-1.48(m,2H), 1.75-1.81(m, 2H), 2.02-2.11(m, 4H), 3.34(t, J=8 Hz, 2H),3.50-4.00(m, 8H), 3.58(t, J=6 Hz, 2H), 3.95(t, J=6 Hz, 2H), 7.45(t, J=8Hz, 1H), 7.61(t, J=8 Hz, 1H), 7.84(d, J=9 Hz, 1H), 8.20(d, J=8 Hz, 1H)

EXAMPLE 15 N-2-(4-p-Fluorobenzyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide##STR112##

The title compound was synthesized by using N-2-(4-p-fluorobenzyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamideobtained in Example 11 and 1-bromopropane according to the same processas in Example 12.

¹ H NMR(CDCl₃) δ 0.95(t, J=7 Hz, 3H), 1.94-2.03(m, 2H), 2.30-2.70(m,8H), 2.64(t, J=6 Hz, 2H), 3.48(s, 2H), 3.53-3.66(m, 2H), 4.35(t, J=7 Hz,2H), 6.97-7.01(m, 2H), 7.24-7.30(m, 3H), 7.35-7.43(m, 3H), 8.37(d, J=8Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 178-188° C.

¹ H NMR(D₂ O) δ 0.86(t, J=7 Hz, 3H), 1.95-2.00(m, 2H), 3.56(t, J=6 Hz,2H), 3.60-3.80(bm, 8H), 3.92(t, J=6 Hz, 2H), 4.48-4.51(m, 2H), 7.30(t,J=9 Hz, 2H), 7.43(t, J=8 Hz, 1H), 7.56-7.61(m, 3H), 7.75(d, J=9 Hz, 1H),8.15(d, J=8 Hz, 1H)

EXAMPLE 16 N-2-(4-p-Fluorobenzyl-1-piperazinyl)ethyl!-1-allylindazole-3-carboxamide##STR113##

The title compound was synthesized by using N-2-(4-p-fluorobenzyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamidecarboxamide obtained in Example 11 and allyl bromide according to thesame process as in Example 12.

¹ H NMR(CDCl₃) δ 2.30-2.70(m, 4H), 2.63(t, J=7 Hz, 2H), 3.48(s, 2H),3.52-3.65(m, 2H), 5.03(d, J=5 Hz, 2H), 5.16(d, J=17 Hz, 1H), 5.26(d,J=10 Hz, 1H), 6.04(ddd, J=5 Hz, 10 Hz, 17 Hz, 1H), 6.97-7.02(m, 2H),7.24-7.30(m, 3H), 7.36(bt, J=5 Hz, 1H), 7.40(d, J=4 Hz, 1H), 8.38(d, J=8Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 193-196° C.

¹ H NMR(D₂ O) δ 3.42(t, J=6 Hz, 2H), 3.55(bs, 8H), 3.87(t, J=6 Hz,2H),4.39(s, 2H), 5.06(d, J=18 Hz, 1H), 5.15(d, J=5 Hz, 2H), 5.29(d, J=10 Hz,1HH), 6.12(ddd, J=5 Hz, 10 Hz, 18 Hz, 1H), 7.28(t, J=9 Hz, 2H), 7.42(t,J=8 Hz, 1H), 7.53-7.60(m, 3H), 7.69(d, J=9 Hz), 8.14(d, J=8 Hz, 1H)

EXAMPLE 17 N-(1-Benzyl-4-piperidyl)-1-n-propylindazole-3-carboxamide##STR114##

To a solution of 1-n-propylindazole-3-carboxylic acid (0.50 g) obtainedin Preparation Example 45 and 1-benzyl-4-piperidylamine (0.51 g) in DMF(20 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.52 g) and 1-hydroxybenzotriazole monohydrate (0.36 g)under ice-cooling, and the mixture was stirred at room temperature for12 hours. To the reaction solution were added water and ethyl acetate,extracted with ethyl acetate, dried over anhydrous potassium carbonate,and the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate:hexane=4:1) to give the title compound (0.70 g) as a yellow oilysubstance. Yield=78%.

¹ H NMR(CDCl₃) δ 0.93(t, J=7 Hz, 3H), 1.58-1.72(m, 2H), 1.96(sext, J=7Hz, 2H), 2.04(d, J=10 Hz, 2H), 2.19(t, J=11 Hz, 2H), 2.86-2.92(m, 2H),3.52(s, 2H), 4.05-4.32(m, 1H), 4.33(t, J=7 Hz,2H), 6.93(d, J=8 Hz, 1H),7.22-7.41(m, 8H), 8.37(t, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 191-194° C.

EXAMPLE 18N-(1-n-Butyl-4-piperidyl)methyl-1-n-propylindazole-3-carboxamide##STR115##

The title compound was synthesized by using(1-n-butyl-4-piperidyl)methylamine obtained in Preparation Example 38and 1-n-propylindazole-3-carboxylic acid obtained in Preparation Example45 according to the same process as in Example 17.

¹ H NMR(CDCl₃) δ 0.91(t. J=8 Hz, 3H), 0.95(t, J=7 Hz, 3H), 1.30(sext,J=7 Hz, 2 Hz), 1.43-1.46(m, 2H), 1.48(sept, J=7 Hz, 2H), 1.62-1.76(m,1H), 1.80(d, J=13 Hz, 2H), 1.93(t, J=11 Hz, 2H), 1.97(sext, J=7 Hz, 2H),2.32(t, J=8 Hz, 2H), 2.97(d, J=11 Hz, 2H), 3.40(t, J=6 Hz, 2H), 4.34(t,J=7 Hz, 2H), 7.10-7.13(m, 1H), 7.37-7.42(m, 2H), 8.38(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 151-152° C.

EXAMPLE 19 N-2-(1-n-Butyl-4-piperidyl)ethyl!-1-n-propylindazole-3-carboxamide##STR116##

The title compound was synthesized by using2-(1-n-butyl-4-piperidyl)ethylamine obtained in Preparation Example 40and 1-n-propylindazole-3-carboxylic acid obtained in Preparation Example45 according to the same process as in Example 17.

¹ H NMR(CDCl₃) δ 0.93(t, J=7 Hz, 3H), 0.95(t, J=7 Hz, 3H), 1.34(sext,J=7 Hz, 3H), 1.49-1.61(m, 1H), 1.63-1.80(m, 4H), 1.91(d,J=15 Hz, 2H),1.97(sext, J=7 Hz, 2H), 2.25-2.40(m, 2H), 2.56-2.66(m, 2H), 3.18-3.29(m,2H), 3.54(q, J=7 Hz, 2H), 4.35(t, J=7 Hz, 2H), 7.01(t, J=6 Hz, 1H),7.25-7.29(m, 1H), 7.39-7.42(m, 2H), 8.36(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 150-151° C.

EXAMPLE 20 N-(4-Piperidyl)-1-n-propylindazole-3-carboxamide ##STR117##

To a solution ofN-(1-benzyl-4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride(0.70 g) obtained in Example 17 in methanol (40 ml) was added asuspension of 10% palladium carbon (2.80 g) in methanol, and the mixturewas stirred at room temperature under hydrogen atmosphere at ordinarypressure for one hour. The reaction solution was filtered off withCelite, and distilled off under reduced pressure to give thehydrochloride (0.50 g) of the title compound. Yield=94%.

¹ H NMR(CDCl₃) δ 0.96(t, J=7 Hz, 3H), 1.99(q, J=7 Hz, 2H), 2.08-2.20(m,2H), 2.20-2.36(m, 2H), 3.09(bs, 2H), 3.50-3.64(m, 2H), 4.20-4.37(m, 1H),4.37(t, J=7 Hz, 2H), 7.27-7.29(m, 1H), 7.40-7.46(m, 2H), 8.31(d, J=8 Hz,1H)

m.p. 188-210° C.

EXAMPLE 21 N-(4-Piperidyl)methyl-1-n-propylindazole-3-carboxamide##STR118##

A solution ofN-(1-methyl-4-piperidyl)methyl-1-n-propylindazole-3-carboxamide (2.00 g)obtained in Example 7 in α-chloroethyl chloroformate (8 ml) was stirredat 70° C. for 6 hours, then methanol (20 ml) was added, and the mixturewas heated under reflux for 2 hours. The reaction solution was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (chloroform:methanol:aqueous ammonia=90:10:1) togive the title compound (0.40g) as a yellow oily substance. Yield=21%.

¹ H NMR(CDCl₃) δ 0.95(t, J=7 Hz, 3H), 1.31-1.35(m, 2H), 1.84(d,J=12 Hz,2H), 1.98(sext, J=7 Hz, 2H), 2.42(bs, 1H), 2.66(td, J=2 Hz,12 Hz, 2H),3.18(d, J=12 Hz, 2H), 3.39(t, J=6 Hz, 2H), 4.34(t, J=7 Hz, 2H),7.10-7.25(m, 1H), 7.25-7.29(m, 1H), 7.40-7.41(m, 2H), 8.37(dd, J=1 Hz, 8Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

EXAMPLE 22 N-(1-Methyl-4-piperidyl)-1-n-propylindazole-3-carboxamide##STR119##

To N-(4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride (0.32g) obtained in Example 20 were added formic acid (0.7 ml) and a 36%aqueous solution of formaldehyde (0.3 ml), and the mixture was stirredat room temperature for 5 hours. Then formic acid (4 ml) and a 36%aqueous solution of formaldehyde (1.6 ml) were further added, and themixture was heated under reflux for 2.5 hours. The reaction solution wasdistilled off under reduced pressure, and to the residue were addedchloroform and aqueous ammonia. After extraction with chloroform, thechloroform layer was washed with saturated aqueous sodium chloride,dried over anhydrous potassium carbonate, and distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform methanol:aqueous ammonia 90:10:2) to give thetitle compound (0.06 g). Yield 18%.

¹ H NMR(CDCl₃) δ 0.95(t, J=7 Hz, 3H), 1.63-1.69(m, 2H), 1.98(sext, J=7Hz, 2H), 2.08(dd, J=2 Hz, 10 Hz, 2H), 2.20(t, J=11 Hz, 2H), 2.33(s, 3H),2.87(d, J=12 Hz, 2H), 4.00-4.10(m, 1H), 4.35(t,J=7 Hz, 2H), 6.88(d, J=8Hz, 1H), 7.24-7.28(m, 1H), 7.37-7.42(m,2H), 8.37(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

EXAMPLE 23 N-(1-n-Butyl-4-piperidyl)-1-n-propylindazole-3-carboxamide##STR120##

To a suspension of N-(4-piperidyl)-1-n-propylindazole-3-carboxamidehydrochloride (0.52 g) obtained in Example 20 in acetonitrile weresuccessively added 50% potassium fluoride--Celite (1.10 g) and1-bromobutane (0.22 ml), and the mixture was heated under reflux for 11hours. The reaction solution was filtered off, distilled off underreduced pressure, and to the residue was added chloroform and saturatedaqueous sodium hydrogencarbonate. After extraction with chloroform, thechloroform layer was dried over anhydrous potassium carbonate, anddistilled off under reduced pressure. The residue was purified by silicagel column chromatography (chloroform:methanol=20:1) to give the titlecompound (0.42 g) as a yellow oily substance. Yield=69%.

¹ H NMR(CDCl₃) δ 0.93(t, J=8 Hz, 3H), 0.95(t, J=8 Hz, 3H), 1.33(sext,J=8 Hz, 2H), 1.46-1.54(m, 2H), 1.61-1.70(d, 2H), 1.98(sext, J=7 Hz, 2H),2.07(bd, J=12 Hz, 2H), 2.16(bt, H=11 Hz, 2H), 2.37(t, J=8 Hz, 2H),2.94(bd, J=12 Hz, 2H), 4.04-4.07(m, 1H), 4.35(t, J=7 Hz, 2H), 6.90(d,J=8 Hz, 1H), 7.24-7.28(m, 1H), 7.37-7.43(m, 2H), 8.37(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

EXAMPLE 24 N-2-(4-Benzyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide##STR121##

To a solution of 2-(4-benzyl-1-piperazinyl)-ethylamine (2.19 g) obtainedin Preparation Example 48 in DMF (150 ml) were successively added atroom temperature 1-n-propylindazole-3-carboxylic acid (2.04 g),triethylamine (1.52 g) and diethyl phosphorocyanidate (1.95 g) withstirring, and the mixture was stirred at room temperature for 12 hours.The reaction solution was distilled off, and the residue obtained waspurified by silica gel column chromatography (ethylacetate-chloroform:methanol aqueous ammonia=10:1:0.05) to give the titlecompound (3.76 g) as a brown oily substance. Yield 90%.

¹ H NMR(CDCl₃) δ 0.96(t, J=7 Hz, 3H), 1.94-2.02(m, 2H), 2.54(bs, 4H),2.59(bs, 4H), 2.66(t, J=6 Hz, 2H), 3.54(s, 2H), 3.59-3.64(m, 2H),4.36(t, J=7 Hz, 2H), 7.24-7.43(m, 9H), 8.37(d, J=8 Hz, 1H)

EXAMPLE 25 N-2-(4-Allyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide EXAMPLE25-1 Synthesis of N-2-(4H-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamidedihydrochloride ##STR122##

To a solution of N-2-(4-benzyl-1-piperazinyl)-ethyl!-1-n-propylindazole-3-carboxamide (0.96g) obtained in Example 24 in methanol (50 ml) in 100 ml Margen typeapparatus for a catalytic reduction were successively added 4Nhydrochloric acid-ethyl acetate solution (2 ml) and 10% palladium-carbonpowder (0.31 g), and the mixture was shaken at room temperature underhydrogen atmosphere for 30 minutes. The insolubles were filtered offwith Celite, and the filtrate was concentrated under reduced pressure togive the title compound (1.10 g) as a white, amorphous substance. Thiscompound was used for the subsequent reaction without purification.

¹ H NMR(CDCl₃) δ 0.86(t, J=7 Hz, 3H), 1.92-2.01(m, 2H), 3.67(t, J=6 Hz,2H), 3.73(bs, 4H), 3.86(bs, 4H), 3.94-4.01(m, 2H), 4.47(t, J=7 Hz, 2H),7.40(t, J=8 Hz, 1H), 7.56(t, J=8 Hz, 1H), 7.71(d, J=9 Hz, 1H), 8.11(d,J=8 Hz, 1H)

EXAMPLE 25-2 Synthesis of N-2-(4-allyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide##STR123##

To a solution of N-2-(4H-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamidedihydrochloride (0.39 g) obtained in Example 25-1 in chloroform (5 ml)were successively added at room temperature triethylamine (0.36 g) andallyl bromide (0.14 g) with stirring, and the mixture was stirred atroom temperature for 15 hours. The reaction solution was diluted withchloroform (10 ml), and the organic layer was washed with aqueous sodiumhydroxide (3 ml). The aqueous layer was extracted with chloroform (10ml×2), then the combined organic layers were dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue (0.28 g)was purified by thin-layer chromatography on silica gel(chloroform:methanol aqueous ammonia=10:1:0.1) to give the titlecompound (0.17 g) as a colorless oily substance. Yield=48%.

¹ H NMR(CDCl₃) δ 0.96(t, J=7 Hz, 3H), 1.95-2.04(m, 2H), 2.52(bs, 4H),2.59(bs, 4H), 2.65(t, J=6 Hz, 2H), 3.02(d, J=6 Hz, 2H), 3.59-3.64(m,2H), 4.36(t, J=7 Hz, 2H), 5.15-5.22(m, 2H), 5.83-5.93(m, 1H),7.25-7.29(m, 1H), 7.38-7.43(m, 3H), 8.37(d, J=8 Hz,1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 190-200° C. (dec.)

¹ H NMR(D₂ O) δ 0.88(t, J=8 Hz, 3H), 1.94-2.03(m, 2H), 3.64(t, J=6 Hz,2H), 3.78(bs, 4H), 3.86(bs, 4H), 3.96-4.00(m, 2H), 4.48(t, J=7 Hz, 2H),4.88(d, J=3 Hz, 2H), 5.72-5.76(m, 2H, 2H), 5.96-6.06(m, 1H, 2H), 7.42(t,J=7 Hz, 1H), 7.58(t, J=7 Hz, 1H), 7.72(d, J=9 Hz, 1H), 8.12(t, J=8 Hz,1H)

EXAMPLE 26 N-2-(4-n-Propyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide##STR124##

The title compound was synthesized by using N-2-(4H-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamidedihydrochloride obtained in Example 25-1 and 1-bromopropane according tothe same process as in Example 25-2.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 0.96(t, J=7 Hz, 3H), 1.48-1.57(m,2H), 1.94-2.03(m, 2H), 2.32(t, J=8 Hz, 2H), 2.52(bs, 4H), 2.59(bs, 4H),2.65(t, J=6 Hz, 2H), 3.59-3.64 (m, 2H), 4.36(t,J=7 Hz, 2H), 7.25-7.29(m,1H), 7.38-7.43(m,3H), 8.37(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 185-194° C. (dec.)

¹ H NMR(D₂ O) δ 0.88(t, J=8 Hz, 3H), 1.06(t, J=7 Hz, 3H), 1.81-1.91(m,2H), 1.94-2.03(m, 2H), 3.33(t, J=8 Hz, 2H), 3.65(t, J=6 Hz, 2H), 3.97(m,2H), 3.60-4.10(br, 8H), 4.48(t, J=7 Hz, 2H), 7.42(t, J=8 Hz, 1H),7.58(t, J=7 Hz, 1H), 7.72(d, J=9 Hz, 1H), 8.12(d, J=8 Hz, 1H)

EXAMPLE 27 N-2-(4-n-Pentyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide##STR125##

The title compound was synthesized by using N-2-(4H-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamidedihydrochloride obtained in Example 25-1 and n-pentyl bromide accordingto the same process as in Example 25-2.

¹ H NMR(CDCl₃) δ 0.90(t, J=7 Hz, 3H), 0.95(t, J=7 Hz, 3H), 1.26-1.36(m,4H), 1.46-1.54(m, 2H), 1.95-2.01(m, 2H), 2.34(t, J=7 Hz, 2H), 2.52(bs,4H), 2.58(bs, 4H), 2.65(t, J=6 Hz, 2H), 3.59-3.64(m, 2H), 4.35(t, J=7Hz, 2H), 7.24-7.29(m, 1H), 7.37-7.42(m, 3H), 8.37(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 175-183° C. (dec.)

¹ H NMR(D₂ O) δ 0.87(t, J=7 Hz, 3H), 0.93(t, J=7 Hz, 3H), 1.40(bs, 4H),1.81(bs, 2H), 1.93-2.02(m, 2H), 3.33(t, J=8 Hz, 2H), 3.50-3.95(br, 8H),3.61(t, J=6 Hz, 2H), 3.95(t, J=6 Hz, 2H), 4.49(t, J=7 Hz, 2H), 7.42(t,J=7 Hz, 1H), 7.58(t, J=7 Hz, 1H), 7.74(d, J=9 Hz,1H), 8.13(d, J=8 Hz,1H)

EXAMPLE 28 N-2-(4-p-Methoxybenzyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamide##STR126##

The title compound was synthesized by using N-2-(4H-1-piperazinyl)ethyl!-1-n-propylindazole-3-carboxamidedihydrochloride obtained in Example 25-1 and p-methoxybenzyl chlorideaccording to the same process as in Example 25-2.

¹ H NMR(CDCl₃) δ 0.96(t, J=7 Hz, 3H), 1.94-2.03(m, 2H), 2.50(bs, 4H),2.56(bs, 4H), 2.64(t, J=6 Hz, 2H), 3.47(s, 2H), 3.58-3.63(m, 2H),3.80(s, 3H), 4.36(t, J=7 Hz, 2H), 6.85(d, J=9 Hz, 2H), 7.23(d, J=9 Hz,2H), 7.25-7.30(m, 1H), 7.38-7.43(m, 3H), 8.37(d,J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 177-190° C. (dec.)

¹ H NMR(D₂ O) δ 0.88(t, J=7 Hz, 3H), 1.94-2.03(m, 2H), 3.60-3.90(br,8H), 3.63(t, J=6 Hz, 2H), 3.92(s, 3H), 3.96(t, J=6 Hz, 2H), 4.46-4.50(m,4H), 7.14(d, J=9 Hz, 2H), 7.42(t, J=8 Hz, 1H), 7.52(d, J=9 Hz, 2H),7.59(t, J=7 Hz, 1H), 7.73(d, J=9 Hz, 1H), 8.12(d, J=8 Hz, 1H)

EXAMPLE 29 N-2-(4-n-Butyl-1-piperazinyl)ethyl!-1-ethylindazole-3-carboxamide##STR127##

The title compound was synthesized by using N-2-(4-n-butyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide carboxamideobtained in Example 10 and ethyl bromide according to the same processas in Example 12.

¹ H NMR(CDCl₃) δ 0.92(t, J=7 Hz, 3H), 1.28-1.37(m, 2H), 1.45-1.52(m,2H), 1.56(t, J=7 Hz, 3H), 2.34(t, J=8 Hz, 2H), 2.53(bs, 4H), 2.58(bs,4H), 2.65(t, J=6 Hz, 2H), 3.59-3.64(m, 2H), 4.45(q,J=7 Hz, 2H),7.25-7.43(m, 4H), 8.38(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 197-206° C. (dec.)

¹ H NMR(D₂ O) δ 0.99(t, J=8 Hz, 3H), 1.40-1.50(m, 2H), 1.53(t, J=7 Hz,3H), 1.76-1.83(m, 2H), 3.35(t, J=8 Hz, 2H), 3.62(t, J=6 Hz, 2H), 3.96(t,J=6 Hz, 2H), 3.60-4.00(br, 8H), 4.55(q, J=7 Hz, 2H), 7.40-7.44(m, 1H),7.58(t, J=8 Hz, 1H), 7.73(d, J=8 Hz, 1H), 8.12(d, J=8 Hz, 1H)

EXAMPLE 30 N-2-(4-n-Butyl-1-piperazinyl)ethyl!-1-isopropylindazole-3-carboxamide##STR128##

The title compound was synthesized by using N-2-(4-n-butyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide obtained inExample 10 and isopropyl bromide according to the same process as inExample 12.

m.p. 82-84° C.

¹ H NMR(CDCl₃) δ 0.92(t, J=7 Hz, 3H), 1.28-1.38(m, 2H), 1.45-1.53(m,2H), 1.62(d, J=7 Hz, 6H), 2.35(t, J=8 Hz, 2H), 2.52(bs, 4H), 2.60(bs,4H), 2.66(t, J=6 Hz, 2H), 3.59-3.64(m, 2H), 4.88(sept, J=7 Hz, 1H),7.25-7.49(m, 4H), 8.38(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 182-194° C. (dec.)

¹ H NMR(D₂ O) δ 1.00(t, J=7 Hz, 3H), 1.42-1.51(m, 2H), 1.62(d, J=7 Hz,6H), 1.77-1.85(m, 2H), 3.36(t, J=8 Hz, 2H), 3.60-4.00(br,8H), 3.65(t,J=6 Hz, 2H), 3.98(t, J=6 Hz, 2H), 5.11(sept, J=7 Hz, 1H), 7.42(t, J=8Hz, 1H), 7.56-7.60(m, 1H), 7.78(d, J=9 Hz, 1H), 8.14(d, J=8 Hz, 1H)

EXAMPLE 31 N-2-(4-n-Butyl-1-piperazinyl)ethyl!-1-cyclopentylindazole-3-carboxamide##STR129##

To a solution of N-2-(4-n-butyl-1-piperazinyl)-ethyl!-1H-indazole-3-carboxamide (0.42 g)obtained in Example 10 in THF (10 ml) were successively addedcyclopentanol (0.16 g), triphenylphosphine (0.41 g) and diethylazodicarboxylate (0.36 g) under ice-cooling, and then the mixture wasstirred at room temperature for 22 hours. The residue obtained byconcentration of the reaction solution was purified by silica gel columnchromatography (methylene chloride:ethylacetate=1:1-chloroform:methanol:aqueous ammonia=10:1:0.05) to give afraction (0.47 g) containing the title compound. This fraction wasseparated by thin-layer chromatography on silica gel(chloroform:methanol:aqueous ammonia=10:1:0.1) to give the titlecompound (0.36 g) as a pale yellow oily substance. Yield=71%.

¹ H NMR(CDCl₃) δ 0.93(t, J=7 Hz, 3H), 1.29-1.38(m, 2H), 1.44-1.51(m, 2H), 1.53-2.26(m, 8H), 2.34(t, J=8 Hz, 2H), 2.58(bs, 8H), 2.65(t, J=6 Hz,2H), 3.57-3.64(m, 2H), 5.00-5.07(m, 1H), 7.24-7.28(m, 1H), 7.37-7.48(m,3H), 8.37(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 157-174° C. (dec.)

¹ H NMR(D₂ O) δ 1.00(t, J=7 Hz, 3H), 1.41-1.51(m, 2H), 1.53-2.29(m,10H), 3.36(t, J=8 Hz, 2H), 3.63(bs, 2H), 3.79(bs, 8H), 3.94-4.00(m, 2H),5.16-5.21(m, 1H), 7.39(t, J=7 Hz, 1H), 7.54(t,J=8 Hz, 1H), 7.73(d, J=8Hz, 1H), 8.09(d, J=7 Hz, 1H)

EXAMPLE 32 N-2-(4-n-Butyl-1-piperazinyl)ethyl!-1-n-propylindazole-3-thiocarboxamide##STR130##

To a solution of N-2-(4-n-butyl-1-piperazinyl)-ethyl!-1-n-propylindazole-3-carboxamide(0.39 g) obtained in Example 3 in toluene (10 ml) was added Lawessonreagent (0.64 g) at room temperature, and the mixture was heated underreflux for one hour. The reaction solution was cooled to roomtemperature, diluted with chloroform (50 ml), and then washed withsaturated aqueous sodium hydrogencarbonate (50 ml). The organic layerwas dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by thin-layer chromatography onsilica gel (chloroform:methanol:aqueous ammonia=8:2:0.2) to give thetitle compound (0.36 g) as a pale yello; oily substance. Yield=88%.

¹ H NMR(CDCl₃) δ 0.91(t, J=7 Hz, 3H), 0.96(t, J=7 Hz, 3H), 1.28-1.37(m,2H), 1.63(bs, 2H), 1.95-2.04(m, 2H), 2.83(bs, 4H), 2.60-3.10(br, 8H;piperazine-H), 3.96(bs, 2H), 4.36(t, J=7 Hz, 2H), 7.28-7.32(m, 1H),7.41-7.42(m, 3H), 8.87(d, J=8 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 178-186° C. (dec.)

¹ H NMR(D₂ O) δ 0.88(t, J=7 Hz, 3H), 1.00(t, J=7 Hz, 3H), 1.45-1.47(m,2H), 1.80(bs, 2H), 1.98-2.00(m, 2H), 3.35(bs, 2H), 3.77(bs, 2H),3.45-4.10(br, 8H), 4.41(bs, 2H), 4.49(bs, 2H), 7.43(t,J=7 Hz, 1H),7.58(t, J=7 Hz, 1H), 7.72(d, J=8 Hz, 1H), 8.56(d, J=8 Hz, 1H)

EXAMPLE 33 3-{N-2-(4-n-Butyl-1-piperazinyl)ethyl!aminomethyl}-1-n-propylindazole##STR131##

To a solution of N-2-(4-n-butyl-1-piperazinyl)-ethyl!-1-n-propylindazole-3-carboxamide(0.36 g) obtained in Example 3 in THF (5 ml) was added lithium aluminumhydride (0.11 g) at room temperature, and the mixture was heated underreflux for 3 hours. The reaction solution was ice-cooled, and weresuccessively added water (0.1 ml), a 15% aqueous sodium hydroxide (0.1ml), water (0.3 ml) and THF (10 ml). After the reaction solution wasstirred at room temperature for 30 minutes, the insolubles were filteredoff with Celite. The filtrate was distilled off under reduced pressure,and the residue was purified by thin-layer chromatography on silica gel(chloroform:methanol:aqueous ammonia=8:2:0.2) to give the title compound(0.14 g) as a pale yellow oily substance. Yield=40%.

¹ H NMR(CDCl₃) δ 0.89-0.94(m, 6H), 1.24-1.35(m, 2H), 1.41-1.49(m, 2H),1.81(bs, 1H), 1.87-1.98(m, 2H), 2.29(t, J=8 Hz, 2H), 2.41(bs, 8H),2.50(t, J=6 Hz, 2H), 2.77(t, J=6 Hz, 2H), 4.17(s, 2H), 4.30(t, J=7 Hz,2H), 7.10-7.14(m, 1H), 7.35-7.36(m, 2H), 7.78(d, J=8.3 Hz, 1H)

Then the title compound was converted to the corresponding hydrochlorideby a conventional method.

m.p. 104-119° C. (dec.)

¹ H NMR(D₂ O) δ 0.84(t, J=7 Hz, 3H), 0.95(t, J=7 Hz, 3H), 1.34-1.44(m,2H), 1.63-1.71(m, 2H), 1.88-1.97(m, 2H), 2.60-3.60(br,8H), 2.96(t, J=6Hz, 2H), 3.11(t, J=8 Hz, 2H), 3.37(t, J=6 Hz, 2H), 4.46(t, J=7 Hz, 2H),4.72(s, 2H), 7.38(t, J=8 Hz, 1H), 7.60(t, J=8 Hz, 1H), 7.73(d, J=9 Hz,1H), 7.93(d, J=8 Hz, 1H)

EXAMPLE 34

The agonist activities of the indazole derivatives of the presentinvention and Mosapride were determined by the following method, thatis, the method determining 5-HT₄ agonist activity by using ratoesophageal tunica muscularis mucosae (Naunyn-Schmiedeberg's Arch.Pharmacol., Vol. 343, 439-446, 1991).

According to the method of the literature, the oesophageal tunicamuscularis mucosae excised from rats were suspended in an organ bathcontaining Krebs-Henseleit solution aerated with a mixed gas (95% O₂, 5%CO₂) and contracted with carbachol (1×10⁻⁶ M). After the contraction wasstabilized, the cumulative administration of the compounds was performedto determine the relaxation of the rat oesophagus pre-contracted withcarbachol. The concentration (ED₅₀) to cause 50% relaxation of thecarbachol-induced contraction was measured. The result is expressed interms of -log ED₅₀ and shown in the following table in which highernumerical value indicates higher activity.

                  TABLE 1                                                         ______________________________________                                        Compound of                              Activity                             Example No.                                                                            R.sub.1 Q       R.sub.2                                                                           m, n , o                                                                            R.sub.3                                                                             (-log ED.sub.50)                     ______________________________________                                        Compound 1                                                                             n-Pr    C = O   III n:3   n-Bu  4.98                                 Compound 2                                                                             n-Pr    C = O   III n:2   Me    4.69                                 Compound 3                                                                             n-Pr    C = O   III n:2   n-Bu  5.62                                 Compound 4                                                                             n-Pr    C = O   IV  o:1   Me    5.01                                 Compound 5                                                                             n-Pr    C = O   IV  o:1   n-Bu  6.36                                 Compound 6                                                                             n-Pr    C = O   V   m:0   n-Bu  5.19                                 Compound 7                                                                             n-Pr    C = O   II  m:1   Me    5.30                                 Compound 8                                                                             n-Pr    C = O   II  m:2   Me    4.97                                 Compound 9                                                                             H       C = O   IV  o:1   p-FBn 5.13                                 Compound 11                                                                            H       C = O   III n:2   p-FBn 4.90                                 Compound 12                                                                            n-Pr    C = O   IV  o:1   p-FBn 5.47                                 Compound 13                                                                            sec-Bu  C = O   III n:2   n-Bu  5.26                                 Compound 14                                                                            3-Pentyl                                                                              C = O   III n:2   n-Bu  5.22                                 Compound 15                                                                            n-Pr    C = O   III n:2   p-FBn 5.17                                 Compound 16                                                                            allyl   C = O   III n:2   p-FBn 5.13                                 Compound 17                                                                            n-Pr    C = O   II  m:0   Bn    5.47                                 Compound 18                                                                            n-Pr    C = O   II  m:1   n-Bu  5.10                                 Compound 19                                                                            n-Pr    C = O   II  m:2   n-Bu  5.89                                 Compound 20                                                                            n-Pr    C = O   II  m:0   H     3.95                                 Compound 21                                                                            n-Pr    C = O   II  m:1   H     4.32                                 Compound 22                                                                            n-Pr    C = O   II  m:0   Me    5.16                                 Compound 23                                                                            n-Pr    C = O   II  m:0   n-Bu  5.55                                 Compound 25                                                                            n-Pr    C = O   III n:2   allyl 5.22                                 Compound 26                                                                            n-Pr    C = O   III n:2   n-Pr  5.05                                 Compound 27                                                                            n-Pr    C = O   III n:2   n-Pentyl                                                                            5.57                                 Compound 28                                                                            n-Pr    C = O   III n:2   p-    5.80                                                                    MeOBn                                      Compound 29                                                                            Et      C = O   III n:2   n-Bu  4.99                                 Compound 30                                                                            i-Pr    C = O   III n:2   n-Bu  5.53                                 Compound 31                                                                            cyc-    C = O   III n:2   n-Bu  5.30                                          Pentyl                                                               Compound 32                                                                            n-Pr    C = S   III n:2   n-Bu  4.98                                 Compound 33                                                                            n-Pr    CH.sub.2                                                                              III n:2   n-Bu  4.53                                 Mosapride                                4.46                                 ______________________________________                                         note) Bn: benzyl                                                              pFBn: pfluorobenzyl                                                           pMeOBn: pmethoxybenzyl                                                   

Finally, examples of pharmaceutical preparations comprising as an activeingredient the present compounds (all the hydrochlorides) are givenbelow.

Pharmaceutical Preparation 1

    ______________________________________                                        Tablets (one tablet)                                                          ______________________________________                                        Compound of Example 3   10 mg                                                 Lactose                 64 mg                                                 Crystalline cellulose   15 mg                                                 Corn starch              7 mg                                                 Hydroxypropylcellulose   3 mg                                                 Magnesium stearate       1 mg                                                 ______________________________________                                    

All components were uniformly mixed to form powders for directcompression. The powders were formed in a rotary tableting machine totablets each having 6 mm in diameter and 100 mg in weight.

Pharmaceutical Preparation 2

    ______________________________________                                        Sugar-coated tablets (one tablet)                                             ______________________________________                                        A:           Compound of Example 3                                                                            10     mg                                                  Lactose            64     mg                                                  Crystalline cellulose                                                                            15     mg                                                  Corn starch        7      mg                                                  Hydroxypropylcellulose                                                                           3      mg                                                  Magnesium stearate 1      mg                                     B:           Saccharose         92     mg                                                  Gum arabic         3.2    mg                                                  Gelatin            0.7    mg                                                  Calcium carbonate  20     mg                                     ______________________________________                                    

All components of the above group A were uniformly mixed to form powdersfor direct compression. The powders were formed in a rotary tabletingmachine to tablets each having 6 mm in diameter and 100 mg in weight.The tablets were coated with the components of the above group Baccording to a conventional method to prepare the sugar-coated tablets.

Pharmaceutical Preparation 3

    ______________________________________                                        Hard capsules (per capsule)                                                   ______________________________________                                        Compound of Example 3   10 mg                                                 Lactose                 64 mg                                                 Crystalline cellulose   15 mg                                                 Corn starch              7 mg                                                 Hydroxypropylcellulose   3 mg                                                 Magnesium stearate       1 mg                                                 ______________________________________                                    

All components were uniformly mixed, pressed and pulverized to preparegranules. The granules were filled in a capsule to prepare a hardcapsule.

Pharmaceutical Preparation 4

    ______________________________________                                        Granules (per divided packet)                                                 ______________________________________                                        A:            Compound of Example 3                                                                            10 mg                                                      Lactose            90 mg                                                      Crystalline cellulose                                                                            50 mg                                                      Corn starch        50 mg                                        B:            Hydroxypropylcellulose                                                                           10 mg                                                      Ethanol             9 mg                                        ______________________________________                                    

After all components of the above group A were uniformly mixed, asolution of the above group B was added. The mixture was kneaded andgranulated by an extrusion granulation method. The granules were thendried in a drier at 50° C. The dried granules were screened to granulesizes of 297 μm-1460 μm to give a granule formulation containing 200 mgnet weight per divided packet.

Pharmaceutical Preparation 5

    ______________________________________                                        Syrups                                                                        ______________________________________                                        Compound of Example 3   1.000 g                                               Refined sugar          30.000 g                                               D-sorbitol, 70 w/v %   25.000 g                                               Ethyl paraoxybenzoate   0.030 g                                               Propyl paraoxybenzoate  0.015 g                                               Flavor                  0.200 g                                               Glycerin                0.150 g                                               96% Ethanol             0.500 g                                               Distilled water        q.s. to make up a                                                             total amount 100 ml                                    ______________________________________                                    

The active ingredient, refined sugar, D-sorbitol, ethyl paraoxybenzoateand propyl paraoxybenzoate were dissolved in 60 g of wiarm water. Aftercooling, glycerol and a solution of flavor in ethanol were added. Thendistilled water was added to the mixture to make up a total amount of100 ml.

Pharmaceutical Preparation 6

    ______________________________________                                        Injections                                                                    ______________________________________                                        Compound of Example 3    1 mg                                                 Sodium chloride         10 mg                                                 Distilled water         q.s. to make up a                                                             total amount 1.0 ml                                   ______________________________________                                    

The active ingredient and sodium chloride were dissolved in distilledwater to make up a total amount of 1.0 ml.

Pharmaceutical Preparation 7

    ______________________________________                                        Suppositories (per piece)                                                     ______________________________________                                        Compound of Example 3    2 g                                                  Polyethylene glycol 4000                                                                              20 g                                                  Glycerol                78 g                                                  ______________________________________                                    

The active ingredient was dissolved in gylcerol. To the solution wasadded polyethylene glycol 4000 and the mixture was warmed to be asolution. The solution was poured into a suppository mold and solidifiedby cooling to prepare suppositories weighing 1.5 g per piece.

Industrial Applicability

The indazole derivatives (I) having a monocyclic amine orpharmaceutically acceptable salts thereof provided by the presentinvention have a 5-HT₄ receptor agonistic activity and are useful forthe treatment of digestive tract disorders derived from chronicgastritis, diabetes mellitus, gastrectomy, peptic ulcer and scleroderma,and digestive tract diseases including reflux esophagitis, irritablebowel syndrome and spurious ileus.

We claim:
 1. An indazole compound of the formula (I): ##STR132## whereinR₁ is hydrogen, C₁ -C₆ alkyl, C₃ -C₆ alkenyl or C₃ -C₆ cycloalkyl;Q iscarbonyl, thiocarbonyl or methylene; and R₂ is a group of the formula(II) or (IV): ##STR133## wherein R₃ is C₁ -C₆ alkyl, C₃ -C₆ alkenyl orbenzyl, of which a phenyl ring thereof is optionally mono- or di-substituted by the same or different halogen or methoxy; m is 0 to 2;and o is 1 or 2; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, where R₁ is C₁ -C₆ alkyl, Q is carbonyl, and R₂ isa group of the formula (II): ##STR134## wherein R₃ is C₁ -C₆ alkyl orbenzyl, of which a phenyl ring thereof is optionally mono- or di-substituted by the same or different halogen atom, and m is 0 to 2, or apharmaceutically acceptable salt thereof.
 3. The compound of claim 1,where R₁ is hydrogen, C₁ -C₆ alkyl or C₃ -C₆ alkenyl; Q is carbonyl, andR₂ is a group of the formula (IV): ##STR135## wherein R₃ is C₁ -C₆ alkylor benzyl, of which a phenyl ring thereof is optionally mono- or di-substituted by the same or different halogen atom, and o is 0 or 2, or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1,which is N-(1-n-butyl-4-piperdyl)-1-n-propylindazole-3-carboxamide, N-2-(1-n-butyl-4-piperidyl)ethyl!-1-n-propylindazole-3-carboxamide, or N-2-(1-n-butyl-4-piperidylidene)ethyl!-1-n-propylindazole-3-carbxamide, ora pharmaceutically acceptable salt thereof.
 5. The compound of claim 4,which is N-(1-n-butyl-4-piperidvl)-1-n-propylindazole-3-carboxamide. 6.The compound of claim 4, which is N-2-(1-n-butyl-4-piperidyl)ethyl!-1-n-propylindazole-3-carboxamide.
 7. Thecompound of claim 4, which is N-2-(1-n-butyl-4-piperidylidene)ethyl!-1-n-propylindazole-3-carboxamide.8. A pharmaceutical composition, which comprises as an active ingredientone or more compounds of claim 1, or a pharmaceutically acceptable saltor salts thereof, in admixture with a pharmaceutically acceptableadditive.
 9. A 5-HT₄ receptor agonist, which comprises as an activeingredient one or more compounds of claim 1, or a pharmaceuticallyacceptable salt or salts thereof, in admixture with a pharmaceuticallyacceptable additive.
 10. A method of treating digestive tract disorders,which comprises administering to a patient in need thereof one or morecompounds of claim 1, or a pharmaceutically acceptable salt or saltsthereof.
 11. The method of claim 10, which promotes gastrointestinalmotility.